Pharmaceutical compounds

ABSTRACT

wherein X1; X2; R1 and R4 are as defined herein.

This application is a divisional of U.S. patent application Ser. No.16/010,831, filed Jun. 18, 2018, which claims priority to GB PatentApplication No.: 1709652.0, filed Jun. 16, 2017, the contents of whichare incorporated herein by reference.

This invention relates to a class of novel 5,3 fused bicyclic compounds,their salts, pharmaceutical compositions containing them and their usein therapy of the human body. In particular, the invention is directedto a class of compounds, which are agonists of the muscarinic M₁ and/orM₄ receptors, and hence are useful in the treatment of Alzheimer'sdisease, schizophrenia, cognitive disorders and other diseases mediatedby the muscarinic M₁/M₄ receptors, as well as the treatment oralleviation of pain.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁mAChR is predominantly expressed post-synaptically in the cortex,hippocampus, striatum and thalamus; M₂ mAChRs are located predominantlyin the brainstem and thalamus, though also in the cortex, hippocampusand striatum where they reside on cholinergic synaptic terminals(Langmead et al., 2008 Br J Pharmacol). However, M₂ mAChRs are alsoexpressed peripherally on cardiac tissue (where they mediate the vagalinnervation of the heart) and in smooth muscle and exocrine glands. M₃mAChRs are expressed at relatively low level in the CNS but are widelyexpressed in smooth muscle and glandular tissues such as sweat andsalivary glands (Langmead et al., 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁mAChR, play a critical role in mediating higher cognitive processing.Diseases associated with cognitive impairments, such as Alzheimer'sdisease, are accompanied by loss of cholinergic neurons in the basalforebrain (Whitehouse et al., 1982 Science). In schizophrenia, which isalso characterised by cognitive impairments, mAChR density is reduced inthe pre-frontal cortex, hippocampus and caudate putamen of schizophrenicsubjects (Dean et al., 2002 Mol Psychiatry). Furthermore, in animalmodels, blockade or lesion of central cholinergic pathways results inprofound cognitive deficits and non-selective mAChR antagonists havebeen shown to induce psychotomimetic effects in psychiatric patients.Cholinergic replacement therapy has largely been based on the use ofacetylcholinesterase inhibitors to prevent the breakdown of endogenousacetylcholine. These compounds have shown efficacy versus symptomaticcognitive decline in the clinic, but give rise to dose-limiting sideeffects resulting from stimulation of peripheral M₂ and M₃ mAChRsincluding disturbed gastrointestinal motility, bradycardia, nausea andvomiting (http://www.drugs.com/pro/donepezil.html;http:/www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁mAChR agonists to target increases in cognitive function. Such effortsresulted in the identification of a range of agonists, exemplified bycompounds such as xanomeline, AF267B, sabcomeline, milameline andcevimeline. Many of these compounds have been shown to be highlyeffective in pre-clinical models of cognition in both rodents and/ornon-human primates. Milameline has shown efficacy versusscopolamine-induced deficits in working and spatial memory in rodents;sabcomeline displayed efficacy in a visual object discrimination task inmarmosets and xanomeline reversed mAChR antagonist-induced deficits incognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder(26.6 million people worldwide in 2006) that affects the elderly,resulting in profound memory loss and cognitive dysfunction. Theaetiology of the disease is complex, but is characterised by twohallmark brain sequelae: aggregates of amyloid plaques, largely composedof amyloid-β peptide (Aβ), and neurofibrillary tangles, formed byhyperphosphorylated tau proteins. The accumulation of Aβ is thought tobe the central feature in the progression of AD and, as such, manyputative therapies for the treatment of AD are currently targetinginhibition of Aβ production. Aβ is derived from proteolytic cleavage ofthe membrane bound amyloid precursor protein (APP). APP is processed bytwo routes, non-amyloidgenic and amyloidgenic. Cleavage of APP byγ-secretase is common to both pathways, but in the former APP is cleavedby an α-secretase to yield soluble APPα. The cleavage site is within theAβ sequence, thereby precluding its formation. However, in theamyloidgenic route, APP is cleaved by β-secretase to yield soluble APPβand also Aβ. In vitro studies have shown that mAChR agonists can promotethe processing of APP toward the soluble, non-amyloidogenic pathway. Invivo studies showed that the mAChR agonist, AF267B, altered disease-likepathology in the 3×TgAD transgenic mouse, a model of the differentcomponents of Alzheimer's disease (Caccamo et al., 2006 Neuron).Finally, the mAChR agonist cevimeline has been shown to give a small,but significant, reduction in cerebrospinal fluid levels of Aβ inAlzheimer's patients, thus demonstrating potential disease modifyingefficacy (Nitsch et al., 2000 Neurol).

Furthermore, preclinical studies have suggested that mAChR agonistsdisplay an atypical antipsychotic-like profile in a range ofpre-clinical paradigms. The mAChR agonist, xanomeline, reverses a numberof dopamine driven behaviours, including amphetamine induced locomotionin rats, apomorphine induced climbing in mice, dopamine agonist driventurning in unilateral 6-OH-DA lesioned rats and amphetamine inducedmotor unrest in monkeys (without EPS liability). It also has been shownto inhibit A10, but not A9, dopamine cell firing and conditionedavoidance and induces c-fos expression in prefrontal cortex and nucleusaccumbens, but not in striatum in rats. These data are all suggestive ofan atypical antipsychotic-like profile (Mirza et al., 1999 CNS DrugRev). Muscarinic receptors have also been implicated in the neurobiologyof addicition. The reinforcing effects of cocaine and other addictivesubstances are mediated by the mesolimbic dopamine system wherebehavioral and neurochemical studies have shown that the cholinergicmuscarinic receptor subtypes play important roles in regulation ofdopaminergic neurotransmission. For example M(4) (−/−) mice demonstratedsignificantly enhanced reward driven behaviour as result of exposure tococaine (Schmidt et al Psychopharmacology (2011) August; 216(3):367-78).Furthermore xanomeline has been dmoenstrated to block the effects ofcocaine in these models.

Xanomeline, sabcomeline, milameline and cevimeline have all progressedinto various stages of clinical development for the treatment ofAlzheimer's disease and/or schizophrenia. Phase II clinical studies withxanomeline demonstrated its efficacy versus various cognitive symptomdomains, including behavioural disturbances and hallucinationsassociated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol).This compound was also assessed in a small Phase II study ofschizophrenics and gave a significant reduction in positive and negativesymptoms when compared to placebo control (Shekhar et al., 2008 Am JPsych). However, in all clinical studies xanomeline and other relatedmAChR agonists have displayed an unacceptable safety margin with respectto cholinergic side effects, including nausea, gastrointestinal pain,diarrhea, diaphoresis (excessive sweating), hypersalivation (excessivesalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Paincan be divided into three different types: acute, inflammatory, andneuropathic. Acute pain serves an important protective function inkeeping the organism safe from stimuli that may produce tissue damagehowever management of post-surgical pain is required. Inflammatory painmay occur for many reasons including tissue damage, autoimmune response,and pathogen invasion and is triggered by the action of inflammatorymediators such as neuropeptides and prostaglandins which result inneuronal inflammation and pain. Neuropathic pain is associated withabnormal painful sensations to non-painful stimuli. Neuropathic pain isassociated with a number of different diseases/traumas such as spinalcord injury, multiple sclerosis, diabetes (diabetic neuropathy), viralinfection (such as HIV or Herpes). It is also common in cancer both as aresult of the disease or a side effect of chemotherapy. Activation ofmuscarinic receptors has been shown to be analgesic across a number ofpain states through the activation of receptors in the spinal cord andhigher pain centres in the brain. Increasing endogenous levels ofacetylcholine through acetylcholinesterase inhibitors, direct activationof muscarinic receptors with agonists or allosteric modulators has beenshown to have analgesic activity. In contrast blockade of muscarinicreceptors with antagonists or using knockout mice increases painsensitivity. Evidence for the role of the M₁ receptor in pain isreviewed by D. F. Fiorino and M. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified whichdisplay improved selectivity for the M₁ mAChR subtype over theperipherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg MedChem Lett; Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al.,2010 ACS Med Chem Lett). Despite increased levels of selectivity versusthe M₃ mAChR subtype, some of these compounds retain significant agonistactivity at both this subtype and the M₂ mAChR subtype. Herein wedescribe a series of compounds which unexpectedly display high levels ofselectivity for the M₁ and/or M₄ mAChR over the M₂ and M₃ receptorsubtypes.

THE INVENTION

The present invention provides compounds having activity as muscarinicM₁ and/or M₄ receptor agonists. More particularly, the inventionprovides compounds that exhibit selectivity for the M₁ or M₄ receptorrelative to the M₂ and M₃ receptor subtypes.

Accordingly, in a first embodiment (Embodiment 1.1), the inventionprovides a compound of the formula (1):

or a salt thereof, wherein:X¹ and X² are saturated hydrocarbon groups which together contain atotal of five to nine carbon atoms and zero or one oxygen atoms andwhich link together such that the moiety:

forms a monocyclic or bicyclic ring system optionally substituted withone or more fluorine atoms;R¹ is selected from OR⁵; NR⁵R⁶; COR⁵; COOR⁵; CONR⁵R⁶; CONR⁵OR⁶;C(═NR⁵)R⁶; C(═NOR⁵)R⁶; OCOR⁵; NR⁷COR⁵; NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶;CH₂OR⁵; CH₂NR⁵R⁶; CH₂COR⁵; CH₂COOR⁵; CH₂CONR⁵R⁶; CH₂CONR⁵OR⁶;CH₂C(═NR⁵)R⁶; CH₂C(═NOR⁵)R⁶; CH₂OCOR⁵; CH₂NR⁷COR⁵; CH₂NR⁷CONR⁵R⁶;CH₂NR⁷COOR⁵; CH₂OCONR⁵R⁶; a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof; and an optionally substituted 4, 5- or 6-membered ringcontaining 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof;R⁴ is a C₁₋₆ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidised formsthereof; andR⁵, R⁶ and R⁷ are the same or different and each is independentlyselected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon group optionallysubstituted with one or more fluorine atoms or optionally substitutedwith a 4, 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof, or R⁵ and R⁶ can bejoined together to form an optionally substituted monocyclic or bicyclicring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof.

1.2 A compound according to Embodiment 1.1 wherein R¹ is OR⁵; NR⁵R⁶;COR⁵; COOR⁵; CONR⁵R⁶; C(═NR⁵)R⁶; CONR⁵OR⁶; C(═NOR⁵)R⁶; NR⁷COR⁵; CH₂OR⁵;CH₂NR⁵R⁶; CH₂COR⁵; CH₂COOR⁵; CH₂CONR⁵R⁶; CH₂CONR⁵OR⁶; CH₂C(═NR⁵)R⁶;CH₂C(═NOR⁵)R⁶; CH₂OCOR⁵; CH₂NR⁷COR⁵; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms;and an optionally substituted 4, 5- or 6-membered ring containing 0, 1,2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

1.3 A compound according to Embodiment 1.1 wherein R¹ is selected fromOR⁵; NR⁵R⁶; COOR⁵; CONR⁵R⁶; CONR⁵OR⁶; C(═NOR⁵)R⁶; CH₂NR⁷COR⁵; a C₁₋₃alkyl group which is optionally substituted with one to three fluorineatoms; and an optionally substituted 5- or 6-membered ring containing 1,or 2 heteroatoms selected from O, N and S and oxidized forms thereof.

1.4 A compound according to Embodiment 1.1 wherein R¹ is selected fromCOOR⁵; CONR⁵R⁶; CONR⁵OR⁶; C(═NOR⁵)R⁶; and an optionally substituted5-membered ring containing 1, or 2 heteroatoms selected from O, N and Sand oxidized forms thereof.

1.5 A compound according to Embodiment 1.1 wherein R¹ is a C₁₋₆non-aromatic hydrocarbon group containing 0, 1 or 2 carbon-carbonmultiple bonds, wherein the hydrocarbon group is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidised forms thereof.

1.6 A compound according to Embodiment 1.1 wherein R¹ is COOR⁵ orCONR⁵R⁶ CONR⁵OR⁶.

1.7 A compound according to Embodiment 1.1 wherein R¹ is an optionallysubstituted 4, 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof.

1.8 A compound according to Embodiment 1.1 wherein R¹ is OR⁵ or NR⁵R⁶.

1.9 A compound according to Embodiment 1.1 wherein R¹ is CH₂OR⁵,CH₂NR⁵R⁶ or CH₂NR⁷COR⁵.

1.10 A compound according to Embodiment 1.1 wherein R¹ is C(═NR⁵)R⁶ orC(═NOR⁵)R⁶;

1.11 A compound according to any one of Embodiments 1.1 to 1.10 whereinR¹ is selected from:

1.12 A compound according to any one of Embodiments 1.1 to 1.11 whereinR⁴ is H or an acyclic C₁₋₄ hydrocarbon group optionally substituted withone or more fluorine atoms.

1.13 A compound according to Embodiment 1.12 wherein R⁴ is H or anacyclic C₁₋₃ hydrocarbon group optionally substituted with one or morefluorine atoms.

1.14 A compound according to Embodiment 1.13 wherein R⁴ is H or a C₁-3alkyl group or a C₁₂ alkynyl group.

1.15 A compound according to Embodiment 1.14 wherein R⁴ is selected fromH, methyl, fluoromethyl, ethyl, ethynyl and 1-propynyl.

1.16 A compound according to Embodiment 1.15 wherein R⁴ is methyl.

1.17 A compound according to Embodiment 1.15 wherein R⁴ is H.

1.18 A compound according to any one of Embodiments 1.1 to 1.17 whereinthe bicyclic ring system formed by the moiety:

is selected from:

-   -   (a) piperidine;    -   (b) azepane;    -   (c) an azabicyclo-heptane, azabicyclo-octane or        azabicyclo-nonane ring system having zero or one oxygen atoms;    -   (d) a 2-aza-spiro[3.3]heptane, 2-aza-spiro[3.4]octane or a        6-aza-spiro[3.4]octane ring system; and    -   (e) a cyclopentanopyrrolidine ring system.

1.19 A compound according to any one of Embodiments 1.1 to 1.18 whereinX¹ and X² together contain four to seven carbon atoms and zero or oneoxygen atoms.

1.20 A compound according to any one of Embodiments 1.1 to 1.19 whereinthe bicyclic ring system formed by the moiety:

is a bridged bicyclic ring system.

1.21 A compound according to Embodiment 1.20 wherein the bridgedbicyclic ring system is an azabicyclo-heptane, azabicyclo-octane orazabicyclo-nonane ring system having zero or one oxygen atoms.

1.22 A compound according to Embodiment 1.21 wherein the bridgedbicyclic ring system is selected from an 2-aza-bicyclo[2.2.2]octane ringsystem, 3-aza-bicyclo[3.1.1]heptane ring system,8-aza-bicyclo[3.2.1]octane ring system, a 9-aza-bicyclo[3.3.1]nonanering system, a 9-aza-3-oxo-bicyclo[3.3.1]nonane ring system, a3-aza-bicyclo[3.2.1]octane ring system and a 6-aza-bicyclo[3.2.1]octanering system.

1.23 A compound according to any one of Embodiments 1.1 to 1.19 whereinthe bicyclic ring system formed by the moiety:

is a spirocyclic ring system.

1.24 A compound according to Embodiment 1.23 wherein the spirocyclicring system is a 2-aza-spiro[3.3]heptane, 2-aza-spiro[3.4]octane or a6-aza-spiro[3.4]octane ring system.

1.25 A compound according to any one of Embodiments 1.1 to 1.19 whereinthe bicyclic ring system formed by the moiety:

is a fused bicyclic ring system.

1.26 A compound according to Embodiment 1.25 wherein the fused bicyclicring system is a cyclopentanopyrrolidine ring system.

1.27 A compound according to any one of Embodiments 1.1 to 1.26 whereinthe bicyclic ring system formed by the moiety:

is selected from ring systems below:

1.28 A compound according to Embodiment 1.1 having the formula (2):

wherein:n is 1 or 2; andR¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.29 A compound according to Embodiment 1.1 having the formula (3):

wherein:R¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.30 A compound according to Embodiment 1.1 having the formula (4):

wherein:R¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.31 A compound according to Embodiment 1.1 having the formula (5):

wherein:R¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.32 A compound according to Embodiment 1.1 having the formula (6):

wherein:R¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.33 A compound according to Embodiment 1.1 having the formula (7):

wherein:R¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.34 A compound according to Embodiment 1.1 having the formula (8):

wherein:R¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.35 A compound according to Embodiment 1.1 having the formula (9):

wherein:R¹ and R⁴ are as defined in any one of Embodiments 1.1 to 1.17.

1.36 A compound according to any one of Embodiments 1.1 to 1.35 whereinR⁵ is selected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon groupoptionally substituted with one or more fluorine atoms or optionallysubstituted with a 4, 5- or 6-membered ring containing 0, 1, 2 or 3heteroatoms selected from O, N and S and oxidized forms thereof, or R⁵and R⁶ can be joined together to form an optionally substitutedmonocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selectedfrom O, N and S and oxidized forms thereof.

1.37 A compound according to any one of Embodiments 1.1 to 1.36 whereinR⁶ is selected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon groupoptionally substituted with one or more fluorine atoms or optionallysubstituted with a 4, 5- or 6-membered ring containing 0, 1, 2 or 3heteroatoms selected from O, N and S and oxidized forms thereof, or R⁵and R⁶ can be joined together to form an optionally substitutedmonocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selectedfrom O, N and S and oxidized forms thereof.

1.38 A compound according to any one of Embodiments 1.1 to 1.37 whereinR¹ is COOR⁵ wherein R⁵ is a non-aromatic C₁₋₆ hydrocarbon group or R¹ isCONR⁵R⁶ wherein R⁵ is a non-aromatic C₁₋₆ hydrocarbon group and R⁶ isselected from hydrogen and a non-aromatic C₁₋₆ hydrocarbon group, or R¹is CONR⁵R⁶ and R⁵ and R⁶ are joined together to form an optionallysubstituted monocyclic or bicyclic ring containing. 0, 1, 2 or 3heteroatoms selected from O, N and S and oxidized forms thereof, or R¹is CONR⁵OR⁶ wherein R⁵ is a non-aromatic C₁₋₆ hydrocarbon group and R⁶is a non-aromatic C₁₋₆ hydrocarbon group.

1.39 A compound according to any one of Embodiments 1.1 to 1.38 whereinR¹ is selected from NR⁵R⁶; CONR⁵R⁶; and CH₂NR⁵R⁶; and R⁵ and R⁶ arejoined together to form an optionally substituted monocyclic or bicyclicring containing. 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof.

1.40 A compound according to Embodiment 1.1 which is as defined in anyone of Examples 1-1 to 12-1.

1.41 A compound according to any one of Embodiments 1.1 to 1.40 having amolecular weight of less than 550, for example less than 500, or lessthan 450.

1.42 A compound according to any one of Embodiments 1.1 to 1.41 which isin the form of a salt.

1.43 A compound according to Embodiment 1.42 wherein the salt is an acidaddition salt.

1.44 A compound according to Embodiment 1.42 or Embodiment 1.43 whereinthe salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of the compounds of theformulas (1) to (4), is used to describe any form of intervention wherea compound is administered to a subject suffering from, or at risk ofsuffering from, or potentially at risk of suffering from the disease ordisorder in question. Thus, the term “treatment” covers bothpreventative (prophylactic) treatment and treatment where measurable ordetectable symptoms of the disease or disorder are being displayed.

The term “effective therapeutic amount” as used herein (for example inrelation to methods of treatment of a disease or condition) refers to anamount of the compound which is effective to produce a desiredtherapeutic effect. For example, if the condition is pain, then theeffective therapeutic amount is an amount sufficient to provide adesired level of pain relief. The desired level of pain relief may be,for example, complete removal of the pain or a reduction in the severityof the pain.

The term “non-aromatic hydrocarbon group” (as in “C₁-5 non-aromatichydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group”refers to a group consisting of carbon and hydrogen atoms and whichcontains no aromatic rings. The hydrocarbon group may be fully saturatedor may contain one or more carbon-carbon double bonds or carbon-carbontriple bonds, or mixtures of double and triple bonds. The hydrocarbongroup may be a straight chain or branched chain group or may consist ofor contain a cyclic group. Thus the term non-aromatic hydrocarbonincludes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenyl alkyl and so on.

The terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl” and “cycloalkenyl”are used in their conventional sense (e.g. as defined in the IUPAC GoldBook) unless indicated otherwise.

The term “cycloalkyl” as used herein, where the specified number ofcarbon atoms permits, includes both monocyclic cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andbicyclic and tricyclic groups. Bicyclic cycloalkyl groups includebridged ring systems such as bicycloheptane, bicyclooctane andadamantane.

In the definitions of R¹, R⁴, R⁵ and R⁶ above, where stated, one or twobut not all, carbon atoms of the non-aromatic hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S andoxidised forms thereof. It will be appreciated that when a carbon atomis replaced by a heteroatom, the lower valencies of the heteroatomscompared to carbon means that fewer atoms will be bonded to theheteroatoms than would have been bonded to the carbon atom that has beenreplaced. Thus, for example, replacement of of a carbon atom (valency offour) in a CH₂ group by oxygen (valency of two) will mean that theresulting molecule will contain two less hydrogen atoms and replacementof a carbon atom (valency of four) in a CH₂ group by nitrogen (valencyof three) will mean that the resulting molecule will contain one lesshydrogen atom.

Examples of a heteroatom replacements for carbon atoms includereplacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with oxygen orsulfur to give an ether —CH₂—O—CH₂— or thioether —CH₂—S—CH₂—,replacement of a carbon atom in a group CH₂—C≡C—H with nitrogen to givea nitrile (cyano) group CH₂—C≡N, replacement of a carbon atom in a group—CH₂—CH₂—CH₂— with C═O to give a ketone —CH₂—C(O)—CH₂—, replacement of acarbon atom in a group —CH₂—CH₂—CH₂— with S═O or SO₂ to give a sulfoxide—CH₂—S(O)—CH₂— or sulfone —CH₂—S(O)₂—CH₂—, replacement of a carbon atomin a —CH₂—CH₂—CH₂— chain with C(O)NH to give an amide —CH₂—CH₂—C(O)—NH—,replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with nitrogen togive an amine —CH₂—NH—CH₂—, and replacement of a carbon atom in a—CH₂—CH₂—CH₂— chain with C(O)O to give an ester (or carboxylic acid)—CH₂—CH₂—C(O)—O—. In each such replacement, at least one carbon atom ofthe hydrocarbon group must remain.

Salts

Many compounds of the formulas (1) to (9) can exist in the form ofsalts, for example acid addition salts or, in certain cases salts oforganic and inorganic bases such as carboxylate, sulfonate and phosphatesalts. All such salts are within the scope of this invention, andreferences to compounds of the formulas (1) to (4) include the saltforms of the compounds as defined in Embodiments 1.42 to 1.44.

The salts are typically acid addition salts.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (as defined in Embodiment 1.43) may be formed with awide variety of acids, both inorganic and organic. Examples of acidaddition salts falling within Embodiment 1.43 include mono- or di-saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1 S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic,methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

Where the compounds of the formula (1) contain an amine function, thesemay form quaternary ammonium salts (Embodiment 1.72), for example byreaction with an alkylating agent according to methods well known to theskilled person. Such quaternary ammonium compounds are within the scopeof formula (1).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecularformula and sequence of bonded atoms but which differ only in thethree-dimensional orientations of their atoms in space. Thestereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the differentorientations of an atom or group about a double bond, as in cis andtrans (Z and E) isomerism about a carbon-carbon double bond, or cis andtrans isomers about an amide bond, or syn and anti isomerism about acarbon nitrogen double bond (e.g. in an oxime), or rotational isomerismabout a bond where there is restricted rotation, or cis and transisomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.73), the inventionprovides a geometric isomer of a compound according to any one ofEmbodiments 1.1 to 1.72.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, andcan exist in the form of two or more optical isomers, references to thecompounds include all optical isomeric forms thereof (e.g. enantiomers,epimers and diastereoisomers), either as individual optical isomers, ormixtures (e.g. racemic mixtures) or two or more optical isomers, unlessthe context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.74) the inventionprovides a compound according to any one of Embodiments 1.1 to 1.73which contains a chiral centre.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and I isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separatedby a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelicacid, (−)-malic acid, and (−)-camphorsulphonic, separating thediastereoisomers by preferential crystallisation, and then dissociatingthe salts to give the individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.75), the inventionprovides compositions containing a compound according to Embodiment 1.74having one or more chiral centres, wherein at least 55% (e.g. at least60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Embodiment1.73 is present as a single optical isomer (e.g. enantiomer ordiastereoisomer).

In one general embodiment (Embodiment 1.76), 99% or more (e.g.substantially all) of the total amount of the compound (or compound foruse) of Embodiment 1.74 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.77) the compound is presentas a single enantiomer.

In another embodiment (Embodiment 1.78), the compound is present as asingle diastereoisomer.

The invention also provides mixtures of optical isomers, which may beracemic or non-racemic. Thus, the invention provides:

1.79 A compound according to Embodiment 1.74 which is in the form of aracemic mixture of optical isomers.

1.80 A compound according to Embodiment 1.74 which is in the form of anon-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1to 1.80 may contain one or more isotopic substitutions, and a referenceto a particular element includes within its scope all isotopes of theelement. For example, a reference to hydrogen includes within its scope¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygeninclude within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and¹⁸O.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention (Embodiment 1.81), the compound of any one of Embodiments1.1 to 1.80 contains no radioactive isotopes. Such compounds arepreferred for therapeutic use.

In another embodiment (Embodiment 1.82), however, the compound of anyone of Embodiments 1.1 to 1.80 may contain one or more radioisotopes.Compounds containing such radioisotopes may be useful in a diagnosticcontext.

Solvates

Compounds of the formula (1) as defined in any one of Embodiments 1.1 to1.82 may form solvates. Preferred solvates are solvates formed by theincorporation into the solid state structure (e.g. crystal structure) ofthe compounds of the invention of molecules of a non-toxicpharmaceutically acceptable solvent (referred to below as the solvatingsolvent). Examples of such solvents include water, alcohols (such asethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can beprepared by recrystallising the compounds of the invention with asolvent or mixture of solvents containing the solvating solvent. Whetheror not a solvate has been formed in any given instance can be determinedby subjecting crystals of the compound to analysis using well known andstandard techniques such as thermogravimetric analysis (TGE),differential scanning calorimetry (DSC) and X-ray crystallography. Thesolvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

Accordingly, in further embodiments 1.83 and 1.84, the inventionprovides:

1.83 A compound according to any one of Embodiments 1.1 to 1.82 in theform of a solvate.

1.84 A compound according to Embodiment 1.83 wherein the solvate is ahydrate.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of theinvention may be anhydrous. Therefore, in another embodiment (Embodiment1.85), the invention provides a compound as defined in any one ofEmbodiments 1.1 to 1.83 in an anhydrous form (e.g. anhydrous crystallineform).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.83 may exist in acrystalline or non-crystalline (e.g. amorphous) state. Whether or not acompound exists in a crystalline state can readily be determined bystandard techniques such as X-ray powder diffraction (XRPD). Crystalsand their crystal structures can be characterised using a number oftechniques including single crystal X-ray crystallography, X-ray powderdiffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR).The behaviour of the crystals under conditions of varying humidity canbe analysed by gravimetric vapour sorption studies and also by XRPD.Determination of the crystal structure of a compound can be performed byX-ray crystallography which can be carried out according to conventionalmethods such as those described herein and as described in Fundamentalsof Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F.Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union ofCrystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b),0-19-85579-2 (h/b)). This technique involves the analysis andinterpretation of the X-ray diffraction of single crystal. In anamorphous solid, the three dimensional structure that normally exists ina crystalline form does not exist and the positions of the moleculesrelative to one another in the amorphous form are essentially random,see for example Hancock et al. J. Pharm. Sci. (1997), 86, 1).

Accordingly, in further embodiments, the invention provides:

1.86 A compound according to any one of Embodiments 1.1 to 1.85 in acrystalline form.

1.80 A compound according to any one of Embodiments 1.1 to 1.85 whichis:

(a) from 50% to 100% crystalline, and more particularly is at least 50%crystalline, or at least 60% crystalline, or at least 70% crystalline,or at least 80% crystalline, or at least 90% crystalline, or at least95% crystalline, or at least 98% crystalline, or at least 99%crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline.

1.88 A compound according to any one of Embodiments 1.1 to 1.85 which isin an amorphous form.

Prodrugs

The compounds of the formula (1) as defined in any one of Embodiments1.1 to 1.88 may be presented in the form of a pro-drug. By “prodrugs” ismeant for example any compound that is converted in vivo into abiologically active compound of the formula (1), as defined in any oneof Embodiments 1.1 to 1.88.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyhydroxyl groups present in the parent compound with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.89), the inventionprovides a pro-drug of a compound as defined in any one of Embodiments1.1 to 1.82 wherein the compound contains a functional group which isconvertible under physiological conditions to form a hydroxyl group oramino group.

Complexes and Clathrates

Also encompassed by formula (1) in Embodiments 1.1 to 1.89 are complexes(e.g. inclusion complexes or clathrates with compounds such ascyclodextrins, or complexes with metals) of the compounds of Embodiments1.1 to 1.89.

Accordingly, in another embodiment (Embodiment 1.90), the inventionprovides a compound according to any one of Embodiments 1.1 to 1.89 inthe form of a complex or clathrate.

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M₁and/or M₄ receptor agonists. The muscarinic activity of the compoundscan be determined using the Phospho-ERK1/2 assay described in Example Abelow.

A significant advantage of compounds of the invention is that they arehighly selective for the M₁ and/or M₄ receptors relative to the M₂ andM₃ receptor subtypes. Compounds of the invention are neither agonistsnor antagonists of the M₂ and M₃ receptor subtypes. For example, whereascompounds of the invention typically have pEC₅₀ values of at least 6(preferably at least 6.5) and E_(max) values of greater than 80(preferably greater than 95) against the M₁ and/or M₄ receptor in thefunctional assay described in Example A, they may have pEC₅₀ values ofless than 5 and E_(max) values of less than 20% when tested against theM₂ and M₃ subtypes in the functional assay of Example A.

Some compounds of the invention have activity at both the M₁ and M₄receptors, and some have activity at the M₄ receptor.

Accordingly, in Embodiments 2.1 to 2.15, the invention provides:

2.1 A compound according to any one of Embodiments 1.1 to 1.90 for usein medicine.

2.2 A compound according to any one of Embodiments 1.1 to 1.90 for useas a muscarinic M₁ and/or M₄ receptor agonist.

2.3 A compound according to any one of Embodiments 1.1 to 1.90 which isa muscarinic M₁ receptor agonist having a pEC₅₀ greater than 6.9 and anE_(max) of at least 80 against the M₁ receptor in the assay of Example Aherein or an assay substantially similar thereto.

2.4 A compound according to Embodiment 2.3 which is a muscarinic M₁receptor agonist having a pEC₅₀ greater than 7.0.

2.5 A compound according to Embodiment 2.3 or Embodiment 2.4 having anE_(max) of at least 90 against the M₁ receptor.

2.6 A compound according to any one of Embodiments 1.1 to 1.90 which isa 30 muscarinic M₁ and M₄ receptor agonist having a pEC₅₀ in the rangefrom 6.0 to 7.8 and an E_(max) of at least 70 against the muscarinic M₁and M₄ receptors in the assay of Example A herein or an assaysubstantially similar thereto.

2.7 A compound according to any one of Embodiments 1.1 to 1.90 which isa muscarinic M₄ receptor agonist having a pEC₅₀ greater than 7.0.

2.8 A compound according to Embodiment 2.6 or Embodiment 2.7 having anE_(max) of at least 90 against the M₄ receptor.

2.9 A compound according to any one of Embodiments 1.1 to 1.90 which isa muscarinic M₄ receptor agonist having a pEC₅₀ in the range from 6.0 to7.8 and an E_(max) of at least 70 against the muscarinic M₄ receptor inthe assay of Example A herein or an assay substantially similar thereto.

2.10 A compound according to any one of Embodiments 2.3 to 2.9 which isselective for the M₁ and M₄ receptor compared to the muscarinic M₂ andM₃ receptors.

2.11 A compound according to Embodiment 2.9 which is selective for theM₄ receptor compared to the muscarinic M₂ and M₃ receptors.

2.12 A compound according to any one of Embodiments 2.3 to 2.5 which isselective for the M₁ receptor compared to the muscarinic M₂, M₃ and M₄receptors.

2.13 A compound according to any one of Embodiments 2.7 or 2.9 which isselective for the M₄ receptor compared to the muscarinic M₁, M₂ and M₃receptors.

2.14 A compound according to any one of Embodiments 2.3 to 2.13 whichhas a pEC₅₀ of less than 5 and an E_(max) of less than 50 against themuscarinic M₂ and M₃ receptor subtypes.

2.15 A compound according to Embodiment 2.14 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the muscarinic M₂ andM₃ receptor subtypes.

2.16 A compound according to any one of Embodiments 1.1 to 1.90 andEmbodiments 2.3 to 2.15 for use in the treatment of a disease orcondition mediated by the muscarinic M₁ and/or M₄ receptors.

By virtue of their muscarinic M₁ and/or M₄ receptor agonist activity,compounds of the invention can be used in the treatment of Alzheimer'sdisease, schizophrenia and other psychotic disorders, cognitivedisorders and other diseases mediated by the muscarinic M₁ and/or M₄receptor, and can also be used in the treatment of various types ofpain.

Accordingly, in Embodiments 2.17 to 2.38, the invention provides:

2.17 A compound according to any one of Embodiments 1.1 to 1.90 for usein the treatment of a cognitive disorder or psychotic disorder.

2.18 A compound for use in according to Embodiment 2.17 wherein thecognitive disorder or psychotic disorder comprises, arises from or isassociated with a condition selected from cognitive impairment, MildCognitive Impairment, frontotemporal dementia, vascular dementia,dementia with Lewy bodies, presenile dementia, senile dementia,Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia,mania, Tourette's syndrome, Alzheimer's disease, progressivesupranuclear palsy, impairment of cognitive functions includingattention, orientation, learning disorders, memory (i.e. memorydisorders, amnesia, amnesic disorders, transient global amnesia syndromeand age-associated memory impairment) and language function; cognitiveimpairment as a result of stroke, Huntington's disease, Pick disease,Aids-related dementia or other dementia states such as multi-infarctdementia, alcoholic dementia, hypotiroidism-related dementia, anddementia associated to other degenerative disorders such as cerebellaratrophy and amyotropic lateral sclerosis; other acute or sub-acuteconditions that may cause cognitive decline such as delirium ordepression (pseudodementia states) trauma, head trauma, age relatedcognitive decline, stroke, neurodegeneration, drug-induced states,neurotoxic agents, age related cognitive impairment, autism relatedcognitive impairment, Down's syndrome, cognitive deficit related topsychosis, and post-electroconvulsive treatment related cognitivedisorders; cognitive disorders due to drug abuse or drug withdrawalincluding nicotine, cannabis, amphetamine, cocaine, Attention DeficitHyperactivity Disorder (ADHD) and dyskinetic disorders such asParkinson's disease, neuroleptic-induced parkinsonism, and tardivedyskinesias, schizophrenia, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid, hallucinogenic and delusionaldisorders, personality disorders, obsessive compulsive disorders,schizotypal disorders, delusional disorders, psychosis due tomalignancy, metabolic disorder, endocrine disease or narcolepsy,psychosis due to drug abuse or drug withdrawal, bipolar disorders andand schizo-affective disorder.

2.19 A compound according to any one of Embodiments 1.1 to 1.90 for usein the treatment of Alzheimer's disease.

2.20 A compound according to any one of Embodiments 1.1 to 1.90 for usein the treatment of Schizophrenia.

2.21 A method of treatment of a cognitive disorder in a subject (e.g. amammalian patient such as a human, e.g. a human in need of suchtreatment), which method comprises the administration of atherapeutically effective dose of a compound according to any one ofEmbodiments 1.1 to 1.90.

2.22 A method according to Embodiment 2.21 wherein the cognitivedisorder comprises, arises from or is associated with a condition asdefined in Embodiment 2.18.

2.23 A method according to Embodiment 2.22 wherein the cognitivedisorder arises from or is associated with Alzheimer's disease.

2.24 A method according to Embodiment 2.22 wherein the cognitivedisorder is Schizophrenia.

2.25 The use of a compound according to any one of Embodiments 1.1 to1.90 for the manufacture of a medicament for the treatment of acognitive disorder.

2.26 The use according to Embodiment 2.25 wherein the cognitive disordercomprises, arises from or is associated with a condition as defined inEmbodiment 2.18.

2.27 The use according to Embodiment 2.26 wherein the cognitive disorderarises from or is associated with Alzheimer's disease.

2.28 The use according to Embodiment 2.26 wherein the cognitive disorderis Schizophrenia.

2.29 A compound according to any one of Embodiments 1.1 to 1.90 for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

2.30 A method of treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.90.

2.31 A compound according to any one of Embodiments 1.1 to 1.90 for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.32 A method of treatment of peripheral disorders such as reduction ofintra ocular pressure in Glaucoma and treatment of dry eyes and drymouth including Sjogren's Syndrome, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.90.

2.33 The use of a compound according to any one of Embodiments 1.1 to1.90 for the manufacture of a medicament for the treatment or lesseningthe severity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica,back pain, head or neck pain, severe or intractable pain, nociceptivepain, breakthrough pain, postsurgical pain, or cancer pain or for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.34 The use of a compound according to any one of Embodiments 1.1 to1.90 for the use in the treatment of skin lesions for example due topemphigus vulgaris, dermatitis herpetiformis, pemphigoid and otherblistering skin conditions.

2.35 The use of a compound according to any one of Embodiments 1.1 to1.90 for the use in treating, preventing, ameliorating or reversingconditions associated with altered gastro-intestinal function andmotility such as functional dyspepsia, irritable bowel syndrome,gastroesophageal acid reflux (GER) and esophageal dysmotility, symptomsof gastroparesis and chronic diarrhea.

2.36 The use of a compound according to any one of Embodiments 1.1 to1.90 for the use in in the treatment of olfactory dysfunction such asBosma-Henkin-Christiansen syndrome, chemical poisoning (e.g. seleniumand silver), hypopituitarism, Kallmann Syndrome, skull fractures, tumourtherapy and underactive thyroid gland.

2.37 The use of a compound according to any one of Embodiments 1.1 to1.90 for the treatment of addiction.

2.38 The use of a compound according to any one of Embodiments 1.1 to1.90 for the treatment of movement disorders such as Parkinson'sdisease, ADHD, Huntingdon's disease, tourette's syndrome and othersyndromes associated with dopaminergic dysfunction as an underlyingpathogenetic factor driving disease.

Methods for the Preparation of Compounds of the Formula (1)

Compounds of the formula (1) can be prepared in accordance withsynthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment (Embodiment 3.1), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.1 to 1.90, which process comprises:

(A) the reaction of a compound of the formula (10):

with a compound of the formula (11):

under reductive amination conditions; wherein R¹, R⁴, X¹ and X² are asdefined in any one of Embodiments 1.1 to 1.44; orB) the reaction of a compound of the formula (12):

with a compound of the formula Cl—C(═O)—O—CH₂—R⁴; wherein R¹, R⁴, X¹ andX² are as defined in any one of Embodiments 1.1 to 1.44; or(C) when it is required to prepare a compound of formula (1) wherein R¹comprises CONR⁵R⁶:the reaction of a compound of the formula (13):

with an amine of the formula R⁵R⁶NH; wherein R represents a suitablegroup such as methyl- or ethyl- and R⁴, R⁵, R⁶, X¹ and X² are as definedin any one of Embodiments 1.1 to 1.44; or(D) when it is required to prepare a compound of formula (1) wherein R¹comprises CONR⁵R⁶:the reaction of a compound of the formula (14):

with an amine of the formula R⁵R⁶NH under amide forming conditions;wherein R⁴, R⁵, R⁶, X¹ and X² are as defined in any one of Embodiments1.1 to 1.44; orE) when it is required to prepare a compound of formula (1) wherein R¹comprises C(═NR⁵)R⁶:the reaction of a compound of the formula (15):

with an amine of the formula R⁵NH₂; wherein R⁴, R⁵, R⁶, X¹ and X² are asdefined in any one of Embodiments 1.1 to 1.44;and optionally:(F) converting one compound of the formula (1) to another compound ofthe formula (1).

In process variant (A), the ketone (11) is reacted with the amine (10)under reductive amination conditions. The reductive amination reactionis typically carried out at ambient temperature to mild heating (e.g. ata temperature of about 20° C. to about 70° C.) using a borohydridereducing agent such as sodium triacetoxy-borohydride (STAB) in a solventsuch as dichloromethane (DCM), dichloroethane (DCE),N,N-dimethylformamide (DMF) or methanol (MeOH) containing an acid suchas acetic acid (AcOH) or trifluoroacetic acid (TFA), or sodiumcyanoborohydride (NaCNBH₃) in combination with zinc chloride (ZnCl₂) ina solvent such as MeOH, or STAB in a solvent such as DCM or DCEcontaining an acid such as AcOH or TFA in combination with titaniumtetraisopropoxide (Ti(O^(i)Pr)₄). Optionally, the amine (10) may bepresent in the reaction as an acid salt such as a hydrogen chloride(HCl), hydrogen bromide (HBr) or a TFA salt, optionally in the presenceof a tertiary base such as triethylamine (TEA) or N,N-diisopropylamine(DIPEA).

When it is required to prepare a compound of formula (1) wherein R¹comprises CONR⁵R⁶, wherein R⁵ and R⁶ are as defined in any one ofEmbodiments 1.1 to 1.44, amines of the formula (10) can be prepared bythe sequence of reactions shown in Scheme 1 below.

Thus, a protected amino ester (16), wherein R represents a suitablegroup such as methyl- or ethyl- and the protecting group PG represents asuitable protecting group such as tert-butyloxycarbonyl (BOC), isreacted with an amine (17), wherein R⁵ and R⁶ are as defined in any oneof Embodiments 1.1 to 1.44 under conditions suitable to effect formationof protected amino amide (18). Typically, such conditions are reactionat a temperature between about 0° C. to about 110° C. in a solvent suchas toluene in combination with a reagent such as trimethylaluminium(Me₃Al), optionally in the presence of a tertiary base such as TEA orDIPEA. It will be well known to the skilled person that other suitableconditions exist to effect formation of protected amino amide (18) fromprotected amino ester (16) and amine (17), such as reaction in thepresence of isopropylmagnesium chloride (^(i)PrMgCl) in a suitablesolvent, or direct heating, optionally in the presence of a suitablesolvent. Once the protected amino amide (18) is formed, the protectinggroup PG can be removed using suitable conditions to form amine (19).For example, when the protecting group PG is BOC, then suitableconditions to effect its removal might be reaction with an acid such asHCl in a solvent such as 1,4-dioxane or diethyl ether (Et₂O), or TFA ina solvent such as DCM.

Alternatively, protected amino amide (18) can be prepared by thesequence of reactions shown in Scheme 2 below.

Thus, a protected amino ester (16), wherein R represents a suitablegroup such as methyl- or ethyl- and the protecting group PG represents asuitable protecting group such as BOC, is reacted under conditionssuitable to effect hydrolysis of the ester to form protected amino acid(20). Typically, such conditions are reaction with a reagent such aslithium hydroxide (LiOH), sodium hydroxide (NaOH) or potassium hydroxide(KOH) in a solvent such as tetrahydrofuran (THF), MeOH, ethanol (EtOH),water (H₂O) or a combination of two or more of the aforementionedsolvents, at a temperature of between about 0° C. to about 100° C. Onceformed, the protected amino acid (20), is reacted with an amine (17),wherein R⁵ and R⁶ are as defined in any one of Embodiments 1.1 to 1.44,under conditions suitable to effect formation of protected amino amide(18). It will be well known to the skilled person that many suitableconditions exist in the art to effect formation of protected amino amide(18) from protected amino acid (20) and amine (17), for example reactionwith an amide coupling reagent such as diisopropylcarbodiimide (DIC),ethyl-(N,N-dimethylamino)propylcarbodiimide hydrochloride (EDC),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (HATU),(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU) or2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P),optionally in the presence of a tertiary base such as TEA or DIPEA,optionally in the presence of 1-hydroxybenzotriazole (HOBt), in asolvent such as DCM, THF or DMF, at a temperature between about 0° C. toabout 100° C.

Alternatively, protected amino amide (18) can be prepared by thesequence of reactions shown in Scheme 3 below.

Thus protected amino acid (20) can be reacted under conditions suitableto effect formation of protected intermediate (21), wherein LGrepresents a suitable leaving group such as chloride (Cl), 1-imidazolyl,or RO(C═O)O (wherein R represents a group such as ethyl- or isobutyl-).Typically, such conditions are reaction with a reagent such as oxalylchloride or thionyl chloride (LG=Cl), 1,1′-carbonyldiimidazole (CDI)(LG=1-imidazolyl) or ethyl- or isobutyl-chloroformate (LG=RO(C═O)O),optionally in the presence of a tertiary base such as TEA or DIPEA,optionally in the presence of a catalyst such as DMF, in a suitablesolvent such as DCM, THF or DMF. Once formed, the protected intermediate(21), is reacted with an amine (17), wherein R⁵ and R⁶ are as defined inany one of Embodiments 1.1 to 1.44 under conditions suitable to effectformation of protected amino amide (18). Typically, such conditions arereaction at a temperature between about 0° C. to about 100° C. in asolvent such as DCM, THF or DMF, optionally in the presence of atertiary base such as TEA or DIPEA.

When it is required to prepare a compound of formula (1) wherein R¹comprises an optionally substituted 5-membered heterocyclic ring, aminesof the formula (10) can be prepared by a combination of the reactionsshown in Scheme 4 below.

Thus, a protected amino ester (22), wherein R represents a suitablegroup such as methyl- or ethyl- and the protecting group PG represents asuitable protecting group such as BOC or benzyloxy carbonyl (CBZ), canbe reacted under conditions suitable to effect formation of protectedWeinreb amide (23) (e.g. reaction with N,O-dimethylhydroxylaminehydrochloride in the presence of a tertiary base such as TEA or DIPEA ina solvent such as toluene in combination with a reagent such as Me₃Al ata temperature between about 0° C. to about 110° C.).

Alternatively, protected Weinreb amide (23) can be formed in two steps:protected amino ester (22) can be reacted under conditions suitable toeffect hydrolysis of the ester to form protected amino acid (27) (e.g.reaction with a reagent such as LiOH, NaOH or KOH in a solvent such asTHF, MeOH, EtOH, H₂O or a combination of two or more of theaforementioned solvents, at a temperature between about 0° C. to about100° C.). Once formed, the protected amino acid (27), can be reacted toeffect formation of protected Weinreb amide (23) (e.g. reaction withN,O-dimethylhydroxylamine hydrochloride in the presence of a tertiarybase such as TEA or DIPEA, in combination with an amide coupling reagentsuch as DIC, EDC, PyBOP, HATU, COMU or T3P, optionally in the presenceof HOBt, in a solvent such as DCM, THF or DMF, at a temperature betweenabout 0° C. to about 100° C.).

Once formed, the protected Weinreb amide (23) can be reacted with anorganolithium or an organomagnesium halide (Grignard reagent) in asuitable solvent such as hexanes, toluene, THF or Et₂O, at a temperaturebetween about −78° C. to about 50° C. to form a protected amino ketone(24), wherein R represents a functional group that is derived from theorganolithium or organomagnesium halide. Once formed, the protectedamino ketone (24) can be reacted further using a combination of chemicaltransformations well described in the art to effect formation ofprotected amine (26), wherein R¹ comprises a suitable optionallysubstituted 5-membered heterocyclic ring. For example, the protectedamino ketone (24) can be reacted with N,N-dimethylformamide dimethylacetal in a solvent such as DMF at a temperature of about 20° C. toabout 100° C., and then reacted further with methylhydrazine sulfate ina solvent such as DMF at a temperature of about 20° C. to about 100° C.to form protected amine (26), wherein R¹ comprises a1-methyl-1H-pyrazol-5-yl group. Alternatively, the protected aminoketone (24) can be reacted with a brominating agent such as bromine,N-bromosuccinimide (NBS), or phenyltrimethylammonium tribromide in asuitable solvent such as MeOH, 1,4-dioxane, DCM or AcOH, optionally inthe presence of an acid such as AcOH or in the presence of a base suchas NaOH, to form protected amino bromide (25). Once formed, protectedamino bromide (25) can be reacted further with thioacetamide in asolvent such as MeOH at a temperature of about 20° C. to about 65° C. toform protected amine (26), wherein R¹ comprises a2-methyl-1,3-thiazol-4-yl group.

Alternatively, protected amino ester (22) or protected amino acid (27)can be reacted directly using a combination of chemical transformationswell described in the art to effect formation of protected amine (26),wherein R¹ comprises a suitable optionally substituted 5-memberedheterocyclic ring such as a 5-methyl-1,3,4-oxadiazol-2-yl group, a5-amino-4H-1,2,4-triazol-3-yl group or a 1H-tetrazol-5-yl group.

Once the protected amine (26) is formed, the protecting group PG can beremoved using suitable conditions to form amine (28), wherein R¹comprises a suitable optionally substituted 5-membered heterocyclic ringas described above. For example, when the protecting group PG is BOC,then suitable conditions to effect its removal might be reaction with anacid such as HCl in a solvent such as 1,4-dioxane or Et₂O, or TFA in asolvent such as DCM. Alternatively, when the protecting group PG is CBZthen suitable conditions to effect its removal might be reaction withhydrogen (H₂) in the presence of a palladium on carbon (Pd/C) catalystin a solvent such as EtOH at a temperature of about 20° C. to about 80°C.

When it is required to prepare a compound of formula (1) wherein R¹comprises NR⁵R⁶, wherein R⁵ and R⁶ are as defined in any one ofEmbodiments 1.1 to 1.44, amines of the formula (10) can be prepared bythe sequence of reactions shown in Scheme 5 below.

Thus, a mono protected diamine (29), wherein PG represents a suitableprotecting group such as BOC or CBZ, is reacted under conditionssuitable to effect formation of protected mono alkylated diamine (30),wherein R⁵ is as defined in any one of Embodiments 1.1 to 1.44.Typically, such conditions might be a nucleophilic substitution reactionwith a suitable electrophile such as an organo-halide (e.g. anorgano-chloride, organo-bromide or organo-iodide) or an organo sulphonicacid ester (e.g. an organo tosylate, organo mesylate or organo triflate)at a temperature between about 0° C. to about 100° C. in a solvent suchas DCM, THF, DMF or N-methylpyrrolidinone (NMP), optionally in thepresence of a tertiary base such as TEA or DIPEA. Alternatively,formation of protected mono alkylated diamine (30) from mono protecteddiamine (29) might be conducted under reductive amination conditions.The reductive amination reaction is typically carried out with asuitable aldehyde or ketone at ambient temperature to mild heating (e.g.at a temperature of about 20° C. to about 70° C.) using a borohydridereducing agent such as STAB in a solvent such as DCM, DCE, DMF or MeOHcontaining an acid such as AcOH or TFA, or NaCNBH₃ in combination withZnCl₂ in a solvent such as MeOH, or STAB in a solvent such as DCM or DCEcontaining an acid such as AcOH or TFA in combination with Ti(O^(i)Pr)₄.Optionally, the mono protected diamine (29) may be present in thereaction as an acid salt such as an HCl, HBr or a TFA salt, optionallyin the presence of a tertiary base such as TEA or DIPEA.

Once formed, the protected mono alkylated diamine (30), is reacted underconditions suitable to effect formation of protected dialkylated diamine(31), wherein R⁵ and R⁶ are as defined in any one of Embodiments 1.1 to1.44. Typically, such conditions might be a nucleophilic substitutionreaction with a suitable electrophile such as an organo-halide (e.g. anorgano-chloride, organo-bromide or organo-iodide) or an organo sulphonicacid ester (e.g. an organo tosylate, organo mesylate or organo triflate)at a temperature between about 0° C. to about 100° C. in a solvent suchas DCM, THF, DMF or NMP, optionally in the presence of a tertiary basesuch as TEA or DIPEA. Alternatively, formation of protected dialkylateddiamine (31) from protected mono alkylated diamine (30) might beconducted under reductive amination conditions. The reductive aminationreaction is typically carried out with a suitable aldehyde or ketone atambient temperature to mild heating (e.g. at a temperature of about 20°C. to about 70° C.) using a borohydride reducing agent such as STAB in asolvent such as DCM, DCE, DMF or MeOH containing an acid such as AcOH orTFA, or NaCNBH₃ in combination with ZnCl₂ in a solvent such as MeOH, orSTAB in a solvent such as DCM or DCE containing an acid such as AcOH orTFA in combination with Ti(O^(i)Pr)₄. Optionally, the protected monoalkylated diamine (30) may be present in the reaction as an acid saltsuch as an HCl, HBr or a TFA salt, optionally in the presence of atertiary base such as TEA or DIPEA.

Once the protected dialkylated diamine (31) is formed, the protectinggroup PG can be removed using suitable conditions to form amine (32).For example, when the protecting group PG is BOC, then suitableconditions to effect its removal might be reaction with an acid such asHCl in a solvent such as 1,4-dioxane or Et₂O, or TFA in a solvent suchas DCM. Alternatively, when the protecting group PG is CBZ then suitableconditions to effect its removal might be reaction with H₂ in thepresence of a Pd/C catalyst in a solvent such as EtOH at a temperatureof about 20° C. to about 80° C.

When it is required to prepare a compound of formula (1) wherein R¹comprises OR⁵, wherein R⁵ is as defined in any one of Embodiments 1.1 to1.44, amines of the formula (10) can be prepared by the sequence ofreactions shown in Scheme 6 below. Thus, an N-protected amino alcohol(33), wherein PG represents a suitable protecting group such as BOC orCBZ, is reacted under conditions suitable to effect formation ofN-protected ether (34), wherein R⁵ is as defined in any one ofEmbodiments 1.1 to 1.44.

Typically, such conditions might be deprotonation of the alcohol moietyusing a suitable base such as sodium hydride (NaH), sodiumbis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide(KHMDS) or potassium tert-butoxide (K^(t)OBu), followed by anucleophilic substitution reaction with a suitable electrophile such asan organo-halide (e.g. an organo-chloride, organo-bromide ororgano-iodide) or an organo sulphonic acid ester (e.g. an organotosylate, organo mesylate or organo triflate) at a temperature betweenabout 0° C. to about 100° C. in a solvent such as THF, DMF or NMP. Oncethe N-protected ether (34) is formed, the protecting group PG can beremoved using suitable conditions to form amine (35). For example, whenthe protecting group PG is BOC, then suitable conditions to effect itsremoval might be reaction with an acid such as HCl in a solvent such as1,4-dioxane or Et₂O, or TFA in a solvent such as DCM. Alternatively,when the protecting group PG is CBZ then suitable conditions to effectits removal might be reaction with H₂ in the presence of a Pd/C catalystin a solvent such as EtOH at a temperature of about 20° C. to about 80°C.

When it is required to prepare a compound of formula (1) wherein R¹comprises CH₂NR⁷COR⁵, wherein R⁵ and R⁷ are as defined in any one ofEmbodiments 1.1 to 1.44, amines of the formula (10) can be prepared bythe sequence of reactions shown in Scheme 7 below. Thus, a protectedamino ester (36), wherein R represents a suitable group such as methyl-or ethyl- and the protecting group PG represents a suitable protectinggroup such as BOC or CBZ, can be reacted under reducing conditionssuitable to effect formation of N-protected amino alcohol (37).Typically, such conditions might be reaction with a borohydride

reducing agent such as lithium borohydride (LiBH₄) or an aluminiumhydride reagent such as lithium aluminium hydride (LAH), in a solventsuch as Et₂O or THF, at a temperature of about −20° C. to about 50° C.Once formed, N-protected amino alcohol (37) can be reacted underoxidising conditions suitable to effect formation of N-protected aminoaldehyde (38). It will be well known to the skilled person that manysuitable conditions exist in the art to effect formation of N-protectedamino aldehyde (38) from N-protected amino alcohol (37), for examplereaction with dimethyl sulphoxide (DMSO) in combination with oxalylchloride in the presence of a tertiary base such as TEA in a solventsuch as DCM at a temperature of about −78° C. to about 20° C. (Swernoxidation conditions), or reaction with Dess-Martin periodinane in asolvent such as DCM at a temperature of about 0° C. to about 20° C.(Dess-Martin oxidation conditions), or reaction with a chromium reagentsuch as pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC)in a solvent such as DCM at a temperature of about 0° C. to about 40° C.

Once formed, N-protected amino aldehyde (38) is reacted with an amine(39), wherein R⁷ is as defined in any one of Embodiments 1.1 to 1.44,under reductive amination conditions to form mono alkylated diamine(40). The reductive amination reaction is typically carried out atambient temperature to mild heating (e.g. at a temperature of about 20°C. to about 70° C.) using a borohydride reducing agent such as STAB in asolvent such as DCM, DCE, DMF or MeOH containing an acid such as AcOH orTFA, or NaCNBH₃ in combination with ZnCl₂ in a solvent such as MeOH, orSTAB in a solvent such as DCM or DCE containing an acid such as AcOH orTFA in combination with Ti(O^(i)Pr)₄. Optionally, the amine (39) may bepresent in the reaction as an acid salt such as an HCl, HBr or a TFAsalt, optionally in the presence of a tertiary base such as TEA orDIPEA. Alternatively, it will be well known to the skilled person thatmany suitable conditions exist in the art to effect formation of monoalkylated diamine (40) from N-protected amino alcohol (37), withoutfirst forming N-protected amino aldehyde (38). For example the alcoholmoiety in N-protected amino alcohol (37) can be converted into asuitable leaving group such as a halogen (e.g. a chloride, bromide oriodide) or a sulphonic acid ester (e.g. a tosylate, mesylate ortriflate) and then reacted further with amine (39) under conditionssuitable to effect a nucleophilic substitution reaction. Once formed,mono alkylated diamine (40) can be reacted with acylating agent (41),wherein R⁵ is as defined in any one of Embodiments 1.1 to 1.44 and LGrepresents an OH group or a suitable leaving group such as Cl,1-imidazolyl, or RO(C═O)O (wherein R represents a group such as ethyl-or isobutyl-), to form N-protected amide (42). For example, when LGrepresents an OH group, then mono alkylated diamine (40) can be reactedwith acylating agent (41) using suitable amide coupling conditions (e.g.using a reagent such as DIC, EDC, PyBOP, HATU, COMU or T3P, optionallyin the presence of a tertiary base such as TEA or DIPEA, optionally inthe presence of HOBt, in a solvent such as DCM, THF or DMF, at atemperature between about 0° C. to about 100° C.). Alternatively, whenLG represents a leaving group such as Cl, 1-imidazolyl, or RO(C═O)O(wherein R represents a group such as ethyl- or isobutyl-), then monoalkylated diamine (40) can be reacted with acylating agent (41) at atemperature between about 0° C. to about 100° C. in a solvent such asDCM, THF or DMF, optionally in the presence of a tertiary base such asTEA or DIPEA. Once the N-protected amide (42) is formed, the protectinggroup PG can be removed using suitable conditions to form amine (43).For example, when the protecting group PG is BOC, then suitableconditions to effect its removal might be reaction with an acid such asHCl in a solvent such as 1,4-dioxane or Et₂O, or TFA in a solvent suchas DCM. Alternatively, when the protecting group PG is CBZ then suitableconditions to effect its removal might be reaction with H₂ in thepresence of a Pd/C catalyst in a solvent such as EtOH at a temperatureof about 20° C. to about 80° C.

Ketones of the formula (11) can be prepared by the sequence of reactionsshown in Scheme 8 below. Thus, a protected amino ketone (44), wherein X¹and X² are as defined in any one of Embodiments 1.1 to 1.44 and PGrepresents a suitable protecting group such as BOC or CBZ, can bedeprotected to give amino ketone (45). For example, when the protectinggroup PG is BOC, then suitable conditions to effect its removal might bereaction with an acid such as HCl in a solvent such as 1,4-dioxane orEt₂O, or TFA in a solvent such as DCM. Alternatively, when theprotecting group PG is CBZ then suitable conditions to effect itsremoval might be reaction with H₂ in the presence of a palladium oncarbon (Pd/C) catalyst in a solvent such as EtOH at a temperature ofabout 20° C. to about 80° C. Once formed, amino ketone (45) can bereacted with chloroformate (46), wherein R⁴ is as defined in any

one of Embodiments 1.1 to 1.44, under suitable conditions to form ketone(11). Typically, such conditions are reaction at a temperature betweenabout 0° C. to about 50° C. in a solvent such as DCM, THF or DMF,optionally in the presence of a tertiary base such as TEA or DIPEA.

In process variant (B), the compound of formula (12) is typicallyreacted with a compound of formula Cl—C(═O)—O—CH₂—R⁴, wherein R⁴ is asdefined in any one of Embodiments 1.1 to 1.44, at a temperature betweenabout 0° C. to about 50° C. in a solvent such as DCM, THF or DMF,optionally in the presence of a tertiary base such as TEA or DIPEA.

Compounds of formula (12) can be prepared by the sequence of reactionsshown in Scheme 9 below. Thus, a compound of formula (10), wherein R¹ isas defined in any one of

Embodiments 1.1 to 1.44, is reacted with a compound of formula (47),wherein X¹ and X² are as defined in any one of Embodiments 1.1 to 1.44and PG represents a suitable protecting group such as BOC or CBZ, underreductive amination conditions to form a compound of formula (48).

The reductive amination reaction is typically carried out at ambienttemperature to mild heating (e.g. at a temperature of about 20° C. toabout 70° C.) using a borohydride reducing agent such as STAB in asolvent such as DCM, DCE, DMF or MeOH containing an acid such as AcOH orTFA, or NaCNBH₃ in combination with ZnCl₂ in a solvent such as MeOH, orSTAB in a solvent such as DCM or DCE containing an acid such as AcOH orTFA in combination with Ti(O^(i)Pr)₄. Optionally, compound (10) may bepresent in the reaction as an acid salt such as an HCl, HBr or a TFAsalt, optionally in the presence of a tertiary base such as TEA orDIPEA. Once formed, the protecting group PG can be removed from acompound of formula (48) to form a compound of formula (12). Forexample, when the protecting group PG is BOC, then suitable conditionsto effect its removal might be reaction with an acid such as HCl in asolvent such as 1,4-dioxane or Et₂O, or TFA in a solvent such as DCM.Alternatively, when the protecting group PG is CBZ then suitableconditions to effect its removal might be reaction with H₂ in thepresence of a Pd/C catalyst in a solvent such as EtOH at a temperatureof about 20° C. to about 80° C.

In process variant (C), the compound of formula (13) is typicallyreacted with an amine of the formula R⁵R⁶NH; wherein R⁵ and R⁶ are asdefined in any one of Embodiments 1.1 to 1.44, at a temperature betweenabout 0° C. to about 110° C. in a solvent such as toluene in combinationwith a reagent such as Me₃Al, optionally in the presence of a tertiarybase such as TEA or DIPEA. It will be well known to the skilled personthat other suitable conditions exist to effect the same transformation,such as reaction in the presence of ^(i)PrMgCl in a suitable solvent, ordirect heating, optionally in the presence of a suitable solvent.

Compounds of formula (13) can be prepared by the reaction shown inScheme 10 below.

Thus, a compound of formula (11) is reacted with an amine of formula(49), wherein R represents a suitable group such as methyl- or ethyl-,under reductive amination conditions to form a compound of formula (13).The reductive amination reaction is typically carried out at ambienttemperature to mild heating (e.g. at a temperature of about 20° C. toabout 70° C.) using a borohydride reducing agent such as STAB in asolvent such as DCM, DCE, DMF or MeOH containing an acid such as AcOH orTFA, or NaCNBH₃ in combination with ZnCl₂ in a solvent such as MeOH, orSTAB in a solvent such as DCM or DCE containing an acid such as AcOH orTFA in combination with Ti(O^(i)Pr)₄. Optionally, compound (49) may bepresent in the reaction as an acid salt such as an HCl, HBr or a TFAsalt, optionally in the presence of a tertiary base such as TEA orDIPEA.

In process variant (D), the compound of formula (14) is typicallyreacted with an amine of the formula R⁵R⁶NH; wherein R⁵ and R⁶ are asdefined in any one of Embodiments 1.1 to 1.44, using suitable amidecoupling conditions. It will be well known to the skilled person thatmany suitable conditions exist in the art to effect formation of anamide from the compound of formula (14) and an amine of the formulaR⁵R⁶NH, for example using a reagent such as DIC, EDC, PyBOP, HATU, COMUor T3P, optionally in the presence of a tertiary base such as TEA orDIPEA, optionally in the presence of HOBt, in a solvent such as DCM, THFor DMF, at a temperature between about 0° C. to about 100° C.Alternatively, the compound of formula (14) can be reacted with an amineof the formula R⁵R⁶NH using the sequence of reactions shown in Scheme 11below.

Thus a compound of formula (14) can be reacted under conditions suitableto effect formation of intermediate (50), wherein LG represents asuitable leaving group such as Cl, 1-imidazolyl, or RO(C═O)O (wherein Rrepresents a group such as ethyl- or isobutyl-). Typically, suchconditions are reaction with a reagent such as oxalyl chloride orthionyl chloride (LG=Cl), CDI (LG=1-imidazolyl) or ethyl- orisobutyl-chloroformate (LG=RO(C═O)O), optionally in the presence of atertiary base such as TEA or DIPEA, optionally in the presence of acatalyst such as DMF, in a suitable solvent such as DCM, THF or DMF.Once formed, the intermediate (50) is reacted with an amine of theformula R⁵R⁶NH, wherein R⁵ and R⁶ are as defined in any one ofEmbodiments 1.1 to 1.44 under conditions suitable to effect formation ofa compound of formula (51). Typically, such conditions are reaction at atemperature between about 0° C. to about 100° C. in a solvent such asDCM, THF or DMF, optionally in the presence of a tertiary base such asTEA or DIPEA.

Compounds of formula (14) can be prepared by the reaction shown inScheme 12 below.

Thus a compound of formula (13), wherein R represents a suitable groupsuch as methyl- or ethyl- and R⁴, X¹ and X² are as defined in any one ofEmbodiments 1.1 to 1.44, can be reacted under conditions suitable toeffect hydrolysis of the ester to form a compound of formula (14). Forexample, reaction with a reagent such as LiOH, NaOH or KOH in a solventsuch as THF, MeOH, EtOH, H₂O or a combination of two or more of theaforementioned solvents, at a temperature between about 0° C. to about100° C.

In process variant (E), the compound of formula (15) is typicallyreacted with an amine of formula R⁵NH₂, wherein R⁵ is as defined in anyone of Embodiments 1.1 to 1.44, under conditions suitable to effectimine formation. It will be well known to the skilled person that manysuitable conditions exist in the art to effect formation of an iminefrom the compound of formula (15) and an amine of the formula R⁵NH₂. Forexample vigorous heating under reflux conditions in a solvent such asbenzene or toluene, optionally in the presence of a catalyst such aspara-toluenesulphonic acid or TFA; in a solvent such as MeOH or EtOH, ata temperature between about 25° C. and reflux temperature, optionally inthe presence of a catalyst such as AcOH or sodium acetate; or in asolvent such as THF or DCM at a temperature between about 25° C. andreflux temperature, optionally in the presence of a desiccant such asanhydrous magnesium sulphate or 4 A molecular sieves. Optionally, theamine of formula R⁵NH₂ may be present in the reaction as an acid saltsuch as an HCl, HBr or a TFA salt, optionally in the presence of atertiary base such as TEA or DIPEA.

Compounds of formula (15) can be prepared by the reactions shown inScheme 13 below.

Thus a compound of formula (13), wherein R represents a suitable groupsuch as methyl- or ethyl- and R⁴, X¹ and X² are as defined in any one ofEmbodiments 1.1 to 1.44, can be reacted with N,O-dimethylhydroxylaminehydrochloride at a temperature between about 0° C. to about 110° C. in asolvent such as toluene in combination with a reagent such as Me₃Al, inthe presence of a tertiary base such as TEA or DIPEA, to form a compoundof formula (52). It will be well known to the skilled person that othersuitable conditions exist to effect the same transformation, such asreaction in the presence of ^(i)PrMgCl in a suitable solvent, in thepresence of a tertiary base such as TEA or DIPEA, or direct heating,optionally in the presence of a suitable solvent, in the presence of atertiary base such as TEA or DIPEA. Alternatively, a compound of formula(14), wherein R⁴, X¹ and X² are as defined in any one of Embodiments 1.1to 1.44, can be reacted with N,O-dimethylhydroxylamine hydrochlorideusing suitable amide coupling conditions. It will be well known to theskilled person that many suitable conditions exist in the art to effectformation of a compound of formula (52) from the compound of formula(14) and N,O-dimethylhydroxylamine hydrochloride, for example using areagent such as DIC, EDC, PyBOP, HATU, COMU or T3P, in the presence of atertiary base such as TEA or DIPEA, optionally in the presence of HOBt,in a solvent such as DCM, THF or DMF, at a temperature between about 0°C. to about 100° C. Alternatively, a compound of formula (50), whereinLG represents a suitable leaving group such as Cl, 1-imidazolyl, orRO(C═O)O (wherein R represents a group such as ethyl- or isobutyl-) andR⁴, X¹ and X² are as defined in any one of Embodiments 1.1 to 1.44, canbe reacted with N,O-dimethylhydroxylamine hydrochloride at a temperaturebetween about 0° C. to about 100° C. in a solvent such as DCM, THF orDMF, in the presence of a tertiary base such as TEA or DIPEA. Onceformed, the compound of formula (52) can be reacted with a Grignardreagent of the formula R⁶MgBr or an organolithium reagent of the formulaR⁶Li, wherein and R⁶ is as defined in any one of Embodiments 1.1 to 1.44under conditions suitable to effect formation of a compound of formula(15). Typically, such conditions are reaction at a temperature betweenabout −78° C. to about 25° C. in a solvent such as THF or Et₂O.

In process variant (F), one compound of the formula (1) can be convertedinto another compound of the formula (1) by methods well known to theskilled person. Examples of synthetic procedures for converting onefunctional group into another functional group are set out in standardtexts such as March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 7th Edition, Michael B. Smith, John Wiley, 2013, (ISBN:978-0-470-46259-1), Organic Syntheses, Online Edition, www.orgsyn.org,(ISSN 2333-3553) and Fiesers' Reagents for Organic Synthesis, Volumes1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Greene's Protective Groups in Organic Synthesis, Fifth Edition,Editor: Peter G. M. Wuts, John Wiley, 2014, (ISBN: 9781118057483).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography),HPLC and SFC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention,there is provided a pharmaceutical composition comprising at least onecompound of the formula (1) as defined in any one of Embodiments 1.1 to1.90 together with at least one pharmaceutically acceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tabletcomposition.

In another embodiment (Embodiment 4.3), the composition is a capsulecomposition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within theseranges, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1-1 to 12-1

The compounds of Examples 1-1 to 12-1 shown in Table 1 below have beenprepared. Their NMR and LCMS properties and the methods used to preparethem are set out in Table 3. The starting materials for each of theExamples are listed in Table 2.

TABLE 1

Example 1-1

Example 1-2

Example 1-3

Example 1-4

Example 2-1

Example 2-2

Example 2-3

Example 2-4

Example 2-5

Example 2-6

Example 2-7

Example 2-8

Example 2-9

Example 2-10

Example 2-11

Example 2-12

Example 2-13

Example 2-14

Example 2-15

Example 2-16

Example 2-17

Example 2-18

Example 2-19

Example 2-20

Example 2-21

Example 2-22

Example 2-23

Example 2-24

Example 2-25

Example 2-26

Example 2-27

Example 2-28

Example 2-29

Example 2-30

Example 3-1

Example 3-2

Example 3-3

Example 3-4

Example 4-1

Example 5-1

Example 5-2

Example 6-1

Example 7-1

Example 7-2

Example 7-3

Example 7-4

Example 7-5

Example 7-6

Example 8-1

Example 8-2

Example 8-3

Example 8-4

Example 8-5

Example 8-6

Example 8-7

Example 8-8

Example 8-9

Example 8-10

Example 9-1

Example 9-2

Example 9-3

Example 10-1

Example 10-2

Example 10-3

Example 10-4

Example 10-5

Example 10-6

Example 10-7

Example 10-8

Example 10-9

Example 10-10

Example 10-11

Example 10-12

Example 10-13

Example 10-14

Example 10-15

Example 11-1

Example 11-2

Example 12-1

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Bruker orJeol instrument. Chemical shift values are expressed in parts permillion (ppm), i.e. (δ)-values. The following abbreviations are used forthe multiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=tripletof triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets,ddt=doublet of doublet of triplets, m=multiplet. Coupling constants arelisted as J values, measured in Hz. NMR and mass spectroscopy resultswere corrected to account for background peaks. Chromatography refers tocolumn chromatography performed using 60-120 mesh silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. TLCfor monitoring reactions refers to TLC run using the specified mobilephase and the Silica gel F254 as a stationary phase from Merck.Microwave-mediated reactions were performed in Biotage Initiator or CEMDiscover microwave reactors.

LCMS Analysis

LCMS analysis of compounds was performed under electrospray conditionsusing the instruments and methods given in the tables below:

LCMS Instrument Details System Instrument Name LC Detector Mass Detector1 Waters 2695 Photo Diode Array ZQ-2000 Detector 2 Waters Acquity HPhoto Diode Array SQ Detector Class 3 Shimadzu Nexera Photo Diode ArrayLCMS-2020 4 Agilent 1290 RRLC Photo Diode Array Agilent 6120 5 HewlettPackard HP G1315A DAD Micromass ZQ 1100 6 Agilent 1260 Photo Diode ArrayAgilent 6120B Infinity LC

LCMS Method Details Flow Method UV Mass Column Rate Name Solvent SystemColumn Gradient Range Range Temp. ° C. ml/min A (A) 5 mM ammonium BEHC18 95:5 at 0.01 min up to 0.40 min, 200-400 nm 100-1200 amu Ambient0.55 acetate + 0.1% formic acid 2.1 × 50 mm, 65:35 at 0.80 min, 45:55 at1.20 min, in water 1.7 μm or 0:100 at 2.50 min up to 3.30 min, (B) 0.1%formic acid in equivalent 95:5 at 3.31 min up to 4.00 min acetonitrile B(A) 20 mM ammonium X-Bridge C18 90:10 at 0.01 min, 10:90 at 5.00 min,200-400 nm  60-1000 amu Ambient 1.00 acetate in water 4.6 × 150 mm,0:100 at 7.00 min up to 11.00 min, (B) methanol 5 μm or 90:10 at 11.01min up to 12.00 min equivalent C (A) 0.1% ammonia in water X-Bridge C1895:5 at 0.01 min, 10:90 at 5.00 min, 200-400 nm  60-1000 amu Ambient1.00 (B) 0.1% ammonia in 4.6 × 50 mm, 5:95 at 5.80 min up to 7.20 min,95:5 acetonitrile 3.5 μm or at 7.21 min up to 10.00 min equivalent D (A)5 mM ammonium BEH C18 95:5 at 0.01 min up to 0.40 min, 200-400 nm100-1200 amu Ambient 0.55 acetate + 0.1% formic acid 2.1 × 50 mm, 60:40at 0.60 min, 40:60 at 1.20 min, in water 1.7 μm or 0:100 at 2.30 min upto 3.00 min, (B) 0.1% formic acid in equivalent 95:5 at 3.01 min up to3.50 min acetonitrile E (A) 5 mM ammonium X-Bridge C18 95:5 at 0.01 min,10:90 at 5.0 min & 200-400 nm  60-1000 amu Ambient 1.00 bicarbonate inwater 4.6 × 50 mm, 5:95 at 5.80 min till 7.20 min, 95:5 at (B)acetonitrile 3.5 μm or 7.21 min up to 10.0 min equivalent F (A) 2.5 Lwater + 2.5 mL Gemini-NX C-18, 98:2 at 0.00 min up to 0.10 min, 5:95230-400 nm 130-800 amu 45 1.50 28% ammonia solution in 2.0 × 30 at 2.50min up to 3.50 min water mm, 3 μm (B) 2.5 L acetonitrile + 135 mLwater + 2.5 mL 28% ammonia solution in water G (A) 2.5 L water + 2.5 mLGemini-NX C-18, 98:2 at 0.00 min up to 0.10 min, 5:95 230-400 nm 130-800amu 45 1.50 28% ammonia solution in 2.0 × 30 at 8.40 min up to 10.00 minwater mm, 3 μm B) 2.5 L acetonitrile + 135 mL water + 2.5 mL 28% ammoniasolution in water H (A) 2.5 L water + 2.5 mL Gemini-NX C-18, 95:5 at0.00 min, 5:95 at 2.00 min up 190-400 nm 150-800 amu 40 1.50 28% ammoniasolution in 2.0 × 30 to 2.50 min, 95:5 at 2.60 min up to water mm, 3 μm3.0 min (B) 2.5 L acetonitrile + 130 mL water + 2.5 mL 28% ammoniasolution in water I (A) 2.5 L water + 2.5 mL Gemini-NX C-18, 98:2 at0.00 min up to 0.10 min, 5:95 190-400 nm 150-800 amu 40 1.50 28% ammoniasolution in 2.0 × 30 at 8.40 min up to 10.00 min water mm, 3 μm (B) 2.5L acetonitrile + 130 mL water + 2.5 mL 28% ammonia solution in waterLCMS data in the experimental section and Tables 2 and 3 are given inthe format: (Instrument system, Method): Mass ion, retention time, UVdetection wavelength.

Compound Purification

Final purification of compounds was performed by preparative reversedphase HPLC, chiral HPLC or chiral SFC using the instruments and methodsdetailed below where data is given in the following format: Purificationtechnique: [phase (column description, column length×internal diameter,particle size), solvent flow-rate, gradient—given as % of mobile phase Bin mobile phase A (over time), mobile phase (A), mobile phase (B)].

Preparative HPLC Purification:

Shimadzu LC-20Aβ binary system with SPD-20A UV detector

Gilson semi preparative HPLC system with 321 pump, GX-271 liquid handlerand Gilson 171 DAD controlled with Gilson Trilution software

Chiral HPLC Purification:

Shimadzu LC-20Aβ binary system with SPD-20A UV detector

Chiral SFC Purification:

Waters SFC 200

Sepiatec 100

Berger Multigram 2

Purification Method A

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min,gradient 5%-30% (over 30 min), 30% (over 5 min), 100% (over 2 min),100%-5% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100%acetonitrile].

Purification Method B

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 17 mL/min,gradient 30%-50% (over 12 min), 100% (over 2 min), 100%-30% (over 2min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method C

Prep HPLC: [Reversed Phase (Gemini C-18, 250×21.2 mm, 5 μm), 15 mL/min,gradient 40%-50% (over 17 min), 100% (over 2 min), 100%-40% (over 3min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method D

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 17 mL/min,gradient 35%-60% (over 12 min), 100% (over 2 min), 100%-35% (over 2min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method E

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min,gradient 35%-56% (over 12 min), 100% (over 1 min), 100%-35% (over 3min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method F

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 14 mL/min,gradient 27% (over 30 min), 100% (over 3 min), 100%-27% (over 3 min),mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method G

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 17 mL/min,gradient 2%-30% (over 30 min), 30% (over 5 min), 95% (over 3 min),95%-2% (over 2 min), mobile phase (A): 0.1% ammonia in water, (B): 100%acetonitrile].

Purification Method H

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 10 mL/min,gradient 5% (over 5 min), 5%-30% (over 5 min), 30% (over 23 min), 100%(over 3 min), 100%-5% (over 4 min), mobile phase (A): 0.1% ammonia inwater, (B): 100% acetonitrile].

Purification Method I

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 5%-34% (over 40 min), 34% (over 2 min), 100% (over 1min), 100%-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonatein water+0.05% ammonia in water, (B) 100% acetonitrile].

Purification Method J

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 75 mL/min, Isochratic (A:B)85:15 (over 6 min), mobile phase (A): 100% liquid CO₂, (B): 0.1%diethylamine in isopropanol:methanol (50:50)].

Purification Method K

Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 15mL/min, gradient 25%-58% (over 18 min), 100% (over 2 min), 100%-25%(over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water,(B): 100% acetonitrile].

Purification Method L

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 20%-30% (over 10 min), 30% (over 13 min), 100% (over 3min), 100%-20% (over 4 min), mobile phase (A): 0.1% ammonia in water,(B) 100% acetonitrile].

Purification Method M

Chiral HPLC: [Normal Phase (CHIRALPAK AD-H, 250×21 mm, 5 μm), 10 mL/min,Isochratic (A:B) 85:15 (over 25 min), mobile phase (A): 0.3%diethylamine in hexane, (B): 0.3% diethylamine in isopropanol:methanol(70:30)].

Purification Method N

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min,gradient 15%-40% (over 32 min), 100% (over 3 min), 100-15% (over 5 min),mobile phase (A): 0.05% ammonia in water, (B): 100% acetonitrile].

Purification Method O

Chiral HPLC: [Normal Phase (CHIRALPAK AD-H, 250×21 mm, 5 μm), 18 mL/min,Isochratic (A:B) 85:15 (over 15 min), mobile phase (A): 0.1%diethylamine in hexane, (B): 0.1% diethylamine in isopropanol].

Purification Method P

Prep HPLC: [Reversed Phase (GEMINI C-18, 250×21.2 mm, 5 μm), 16 mL/min,gradient 35%-60% (over 18 min), 100% (over 2 min), 100%-35% (over 2min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100%acetonitrile].

Purification Method Q

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL/min, Isochratic (A:B)85:15 (over 5 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% TFA inisopropanol].

Purification Method R

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 14 mL/min,gradient 50% (over 18 min), 100% (over 3 min), 100%-50% (over 4 min),mobile phase (A): 0.1% ammonia in water, (B): acetonitrile:methanol(50:50)].

Purification Method S

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL/min, Isochratic (A:B)80:20 (over 5 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% TFA inisopropanol].

Purification Method T

Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 15mL/min, gradient 45%-60% (over 20 min), 100% (over 3 min), 100%-45%(over 2 min), mobile phase (A): 0.1% ammonia in water, (B): 100%acetonitrile].

Purification Method U

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 5% (over 5 min), 5%-24% (over 3 min), 24% (over 34min), 100% (over 3 min), 100%-5% (over 3 min), mobile phase (A): 0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method V

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 5% (over 5 min), 5%-30% (over 3 min), 30%-35% (over 37min), 100% (over 2 min), 100%-5% (over 3 min), mobile phase (A): 0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method W

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 40%-55% (over 10 min), 100% (over 2 min), 100%-40%(over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B)100% acetonitrile].

Purification Method X

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 50 mL/min, Isochratic (A:B)80:20 (over 5 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% TFA inisopropanol].

Purification Method Y

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min,gradient 30%-50% (over 20 min), 100% (over 2 min), 100%-30% (over 2min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100%acetonitrile].

Purification Method Z

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 150×19 mm, 5 μm), 15mL/min, gradient 15%-65% (over 16 min), 100% (over 2 min), 100%-15%(over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B)100% acetonitrile].

Purification Method AA

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B)85:15 (over 10 min), mobile phase (A): 100% liquid CO₂, (B):isopropanol].

Purification Method AB

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 17mL/min, gradient 10%-30% (over 40 min), 30% (over 3 min), 100% (over 2min), 100%-10% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonatein water+0.05% ammonia in water, (B) 100% acetonitrile].

Purification Method AC

Prep HPLC: [Reversed Phase (GEMINI C-18, 250×21.2 mm, 5 μm), 16 mL/min,gradient 45%-80% (over 12 min), 100% (over 2 min), 100%-45% (over 2min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method AD

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 15%-45% (over 28 min), 100% (over 2 min), 100%-15%(over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05%ammonia in water, (B) 100% acetonitrile].

Purification Method AE

SFC: [(CHIRALCEL AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B)85:15 (over 12 min), mobile phase (A): 100% liquid CO₂, (B): 0.1%diethylamine in isopropanol:methanol (50:50)].

Purification Method AF

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min,gradient 38%-45% (over 16 min), 100% (over 2 min), 100%-38% (over 4min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method AG

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 60 mL/min, Isochratic (A:B)80:20 (over 6 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% ammoniain isopropanol].

Purification Method AH

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 22% (over 30 min), 100% (over 2 min), 100%-22% (over 3min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100%acetonitrile].

Purification Method AI

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 12 mL/min,gradient 27% (over 35 min), 100% (over 2 min), 100%-27% (over 3 min),mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method AJ

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 11 mL/min,gradient 33% (over 25 min), 100% (over 2 min), 100%-33% (over 3 min),mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100%acetonitrile].

Purification Method AK

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 18 mL/min,gradient 35% (over 85 min), 100% (over 2 min), 100%-35% (over 8 min),mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method AL

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 40% (over 25 min), 100% (over 2 min), 100%-40% (over 3min), mobile phase (A): 0.02% ammonia in water, (B) 100% acetonitrile].

Purification Method AM

Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 15mL/min, gradient 60%-92% (over 16 min), 100% (over 2 min), 100%-60%(over 4 min), mobile phase (A): 0.1% ammonia in water, (B): 100%acetonitrile].

Purification Method AN

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 10%-50% (over 10 min), 50% (over 15 min), 100% (over 2min), 100%-10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonatein water, (B) 100% acetonitrile].

Purification Method AO

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min,gradient 30% (over 27.5 min), 100% (over 2.5 min), 100%-30% (over 4min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method AP

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 15% (over 2 min), 15%-35% (over 8 min), 35% (over 18min), 100% (over 3 min), 100%-15% (over 4 min), mobile phase (A): 10 mMammonium bicarbonate in water, (B) 100% acetonitrile].

Purification Method AQ

Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 17mL/min, gradient 20%-55% (over 20 min), 100% (over 2 min), 100%-20%(over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100%acetonitrile].

Purification Method AR

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min,gradient 60%-70% (over 15 min), 100% (over 2 min), 100%-60% (over 3min), mobile phase (A): 0.1% ammonia in water, (B):acetonitrile:methanol (50:50)].

Purification Method AS

SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 70:30(over 15 min), mobile phase (A): 100% liquid CO₂, (B): 0.3% diethylaminein methanol].

Purification Method AT

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 150×19 mm, 5 μm), 15mL/min, gradient 35%-40% (over 15 min), 100% (over 3 min), 100%-35%(over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water+0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method AU

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min,gradient 20%-35% (over 20 min), 100% (over 2 min), 100%-20% (over 2min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammoniain water, (B): 100% acetonitrile].

Purification Method AV

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 85:15(over 5 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol:methanol (50:50)].

Purification Method AW

Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 150×20 mm, 5 μm), 15mL/min, gradient 50% (over 17 min), 100% (over 2 min), 100%-50% (over 4min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammoniain water, (B): 100% acetonitrile].

Purification Method AX

SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 88:12(over 11 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol:methanol (50:50)].

Purification Method AY

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 20%-70% (over 20 min), 100% (over 2 min), 100%-20%(over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method AZ

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B)85:15 (over 4.5 min), mobile phase (A): 100% liquid CO₂, (B): 0.1%diethylamine in methanol].

Purification Method BA

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 150×19 mm, 5 μm), 15mL/min, gradient 22%-45% (over 40 min), 100% (over 2 min), 100%-22%(over 3 min), mobile phase (A): 0.02% ammonia in water, (B) 100%acetonitrile].

Purification Method BB

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 20%-50% (over 8.7 min), 50% (over 0.5 min), 50%-100% (over 0.2min), 100% (over 1 min), 100%-20% (over 0.2 min), 20% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method BC

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 30%-50% (over 27 min), 50%-100% (over 2 min), 100%(over 1 min), 100%-30% (over 1 min), mobile phase (A): 0.02% ammonia inwater, (B) 100% acetonitrile].

Purification Method BD

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 30%-35% (over 28 min), 35%-55% (over 7 min), 100% (over2 min), 100%-30% (over 2 min), mobile phase (A): 0.02% ammonia in water,(B) 100% acetonitrile].

Purification Method BE

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 15%-65% (over 18 min), 100% (over 2 min), 100%-15%(over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method BF

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 43% (over 14 min), 43%-70% (over 1 min), 70% (over 7min), 100% (over 1 min), 100%-43% (over 2 min), mobile phase (A): 10 mMammonium bicarbonate in water, (B) 100% acetonitrile].

Purification Method BG

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min,gradient 40%-55% (over 16 min), 55% (over 2 min), 100% (over 3 min),100%-40% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B):100% acetonitrile].

Purification Method BH

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 30%-50% (over 8.7 min), 50% (over 0.5 min), 50%-100% (over 0.2min), 100% (over 1 min), 100%-30% (over 0.2 min), 30% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method BI

SFC: [(CHIRALPAK AS-H, 250×20 mm, 5 μm), 50 mL/min, Isochratic (A:B)80:20, mobile phase (A): 100% liquid CO₂, (B): 0.1% ammonia in ethanol].

Purification Method BJ

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 40%-60% (over 8.7 min), 60% (over 0.5 min), 60%-100% (over 0.2min), 100% (over 1 min), 100%-40% (over 0.2 min), 40% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method BK

SFC: [(LUX C4, 250×21.2 mm, 5 μm), 50 mL/min, Isochratic (A:B) 70:30,mobile phase (A): 100% liquid CO₂, (B): 0.1% ammonia in methanol].

Purification Method BL

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min,gradient 25%-60% (over 15 min), 100% (over 3 min), 100%-25% (over 2 min)mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100%acetonitrile].

Purification Method BM

SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B)80:20 (over 15 min), mobile phase (A): 100% liquid CO₂, (B):isopropanol:acetonitrile (50:50)].

Purification Method BN

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 35%-50% (over 17 min), 100% (over 2 min), 100%-35%(over 2 min), mobile phase (A): 0.1% ammonia in water, (B) 100%acetonitrile].

Purification Method BO

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 50%-70% (over 8.7 min), 70% (over 0.5 min), 70%-100% (over 0.2min), 100% (over 1 min), 100%-50% (over 0.2 min), 50% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method BP

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 12 mL/min,gradient 55% (over 28 min), 100% (over 2 min), 100%-55% (over 5 min),mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100%acetonitrile].

Purification Method BQ

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min,gradient 20%-45% (over 40 min), 100% (over 3 min), 100%-20% (over 3min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100%acetonitrile].

Purification Method BR

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min,gradient 10%-30% (over 10 min), 30% (over 22 min), 100% (over 2 min),100%-10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate inwater+0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method BS

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 20%-50% (over 20 min), 50% (over 12 min), 100% (over 2min), 100%-20% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonatein water, (B) acetonitrile:methanol (50:50)].

Purification Method BT

Chiral HPLC: [Normal Phase (CHIRALPAK IC, 250×21 mm, 5 μm), 18 mL/min,Isochratic (A:B) 75:25 (over 38 min), mobile phase (A): 0.1%diethylamine in hexane, (B): 0.1% diethylamine in isopropanol:methanol(50:50)].

Purification Method BU

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 17 mL/min,gradient 30% (over 22 min), 100% (over 2 min), 100%-30% (over 3 min),mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia inwater, (B): 100% acetonitrile].

Purification Method BV

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 15%-40% (over 10 min), 40% (over 3 min), 100% (over 2min), 100%-15% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonatein water, (B) 100% acetonitrile].

Purification Method BW

SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B)80:20 (over 13 min), mobile phase (A): 100% liquid CO₂, (B): 0.1%diethylamine in isopropanol:methanol (50:50)].

Purification Method BX

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 15%-40% (over 18 min), 100% (over 2 min), 100%-15%(over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B)100% acetonitrile].

Purification Method BY

SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 70:30(over 10 min), mobile phase (A): 100% liquid CO₂, (B): 0.3% diethylaminein isopropanol:acetonitrile (60:40)].

Purification Method BZ

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 20%-35% (over 18 min), 100% (over 2 min), 100%-20%(over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method CA

SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 75 mL/min, Isochratic (A:B)85:15 (over 20 min), mobile phase (A): 100% liquid CO₂, (B): 0.1%diethylamine in isopropanol:methanol (50:50)].

Purification Method CB

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 25-35% (over 20 min), 100% (over 2 min), 100%-25% (over1 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method CC

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 87:13(over 5 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol:methanol (50:50)].

Purification Method CD

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 5%-40% (over 20 min), 100% (over 2 min), 100%-5% (over3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method CE

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 85:15(over 6 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein methanol].

Purification Method CF

SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 75:25(over 21 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol].

Purification Method CG

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 5%-37% (over 27 min), 37% (over 2 min), 100% (over 2min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonatein water+0.1% ammonia in water, (B) 100% acetonitrile].

Purification Method CH

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 80 mL/min, Isochratic (A:B) 85:15(over 5 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol:methanol (50:50)].

Purification Method CI

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 0%-55% (over 20 min), 100% (over 2 min), 100%-0% (over3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1%ammonia in water, (B) 100% acetonitrile].

Purification Method CJ

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 50 mL/min, Isochratic (A:B) 85:15(over 6 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein methanol].

Purification Method CK

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min,gradient 22% (over 60 min), 100% (over 5 min), 100%-22% (over 4 min),mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia inwater, (B): 100% acetonitrile].

Purification Method CL

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 10-40% (over 20 min), 40% (over 2 min), 100% (over 2min), 100-10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonatein water+0.1% ammonia in water, (B) 100% acetonitrile].

Purification Method CM

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 88:12(over 10 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein methanol].

Purification Method CN

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL/min,gradient 15%-16.5% (over 15 min), 16.5% (over 13 min), 100% (over 4min), 100%-15% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonatein water, (B): 100% acetonitrile].

Purification Method CO

SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 80 mL/min, Isochratic (A:B)75:25 (over 13 min), mobile phase (A): 100% liquid CO₂, (B): 0.1%diethylamine in methanol].

Purification Method CP

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min,gradient 5%-25% (over 29 min), 25% (over 9 min), 100% (over 3 min),100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate inwater+0.05% ammonia in water, (B): 100% acetonitrile].

Purification Method CQ

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 75:25(over 14 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol:methanol (50:50)].

Purification Method CR

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15mL/min, gradient 0%-33% (over 26 min), 100% (over 2 min), 100%-0% (over2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1%ammonia in water, (B): 100% acetonitrile].

Purification Method CS

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 87:13(over 8 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol:methanol (50:50)].

Purification Method CT

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL/min,gradient 13%-40% (over 32 min), 100% (over 2 min), 100%-13% (over 2min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammoniain water, (B): 100% acetonitrile].

Purification Method CU

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 17mL/min, gradient 5%-23% (over 40 min), 23% (over 30 min), 100% (over 3min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonatein water+0.05% ammonia in water, (B) 100% acetonitrile].

Purification Method CV

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min,gradient 20%-45% (over 18 min), 45% (over 2 min), 100% (over 2 min),100%-20% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate inwater+0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method CW

SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 70:30(over 20 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein methanol].

Purification Method CX

Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16mL/min, gradient 5%-37% (over 27 min), 37% (over 2 min), 100% (over 2min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonatein water+0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method CY

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 11 mL/min,gradient 5%-65% (over 25 min), 65% (over 5 min), 100% (over 2 min),100%-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate inwater+0.1% ammonia in water, (B): 100% acetonitrile].

Purification Method CZ

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min,gradient 30%-45% (over 16 min), 100% (over 2 min), 100%-30% (over 5min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammoniain water, (B): 100% acetonitrile].

ABBREVIATIONS

-   aq.=aqueous-   conc.=concentrated-   DCM=dichloromethane-   DIPEA=diisopropylethylamine-   DMF=dimethylformamide-   DMSO=dimethylsulfoxide-   ES(I)=electro spray ionisation-   EtOAc=ethyl acetate-   h=hour(s)-   H₂O=water-   HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HCl=hydrogen chloride, hydrochloric acid-   HPLC=high performance liquid chromatography-   LC=liquid chromatography-   MeOH=Methanol-   min(s)=minute(s)-   MS═mass spectrometry-   nm=nanometre(s)-   NMR=nuclear magnetic resonance-   SFC=supercritical fluid chromatography-   STAB=sodium triacetoxyborohydride-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

Synthesis of Intermediates Route 1 Procedure for the Preparation ofIntermediate 46, methyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate

tert-Butyl 6-oxo-2-azaspiro [3.4] octane-2-carboxylate, (Intermediate44) (120 mg, 0.533 mmol) was dissolved in DCM (2 mL) at 0° C. and TFA (1mL) was added. The reaction mixture was allowed to warm to roomtemperature and was stirred for 2 h, then concentrated in-vacuo. Theresidue was dried by co-evaporation from diethyl ether (3×10 mL) to give2-azaspiro[3.4]octan-6-one trifluoroacetic acid salt (120 mg, 100%) as agum.

LCMS (System 1, Method E): m/z 125 (M+H)⁺ (ES+), at 0.60 min, 202 nm.

2-Azaspiro[3.4]octan-6-one trifluoroacetic acid salt (60 mg, 0.251 mmol)was dissolved in DCM (5 mL) and triethylamine (0.2 mL, 1.25 mmol) wasadded at 0° C. Methyl chloroformate, (Intermediate 45) (94 mg, 0.37mmol) was added at 0° C. and the reaction mixture was allowed to warm toroom temperature and was stirred for 2 h. The mixture was concentratedin-vacuo and the residue was partitioned between H₂O (25 mL) and EtOAc(25 mL). The aqueous layer was further extracted with EtOAc (2×10 mL)and the combined organic layers were dried (Na₂SO₄) and the solvent wasremoved in-vacuo to give methyl6-oxo-2-azaspiro[3.4]octane-2-carboxylate, (Intermediate 46) (30 mg,34%) as an oil.

The data for Intermediate 46 are in Table 2.

Route 2 Procedure for the Preparation of Intermediate 53, ethyl5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate

tert-Butyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate, (Intermediate51) (120 mg, 0.53 mmol) was stirred in HCl solution in 1,4-dioxane (4 M,0.5 mL) for 1 h at room temperature. The mixture was concentratedin-vacuo and triturated with diethyl ether (2×2 mL) to give2-azabicyclo[2.2.2]octan-5-one hydrochloride salt (80 mg, 93%) as asolid.

LCMS (System 2, Method A): m/z 126 (M+H)⁺ (ESI+ve), at 2.01 min, 250 nm.

2-Azabicyclo[2.2.2]octan-5-one hydrochloride salt (80 mg, 0.49 mmol) andtriethylamine (0.2 mL, 1.48 mmol) were dissolved in DCM (4 mL) and ethylchloroformate, (Intermediate 52) (0.07 mL, 0.74 mmol) was added at 0° C.The mixture was stirred at room temperature for 2 h and then partitionedbetween cold H₂O (15 mL) and EtOAc (15 mL). The aqueous layer wasfurther extracted with EtOAc (2×15 mL), and the combined organic layerswere dried (Na₂SO₄) and the solvent was removed in-vacuo to give ethyl5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate, (Intermediate 53) (90 mg,96%) as a gum.

The data for Intermediate 53 are in Table 2.

General Synthetic Procedures Route A Typical Procedure for thePreparation of Amines as Exemplified by the Preparation of Example 1-1,ethyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate

Ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate,(Intermediate 1) (0.12 g, 0.62 mmol), ethyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, (Intermediate 2) (0.14 g,0.82 mmol), triethylamine (0.082 g, 0.82 mmol) and zinc chloride (4.2mg, 0.031 mmol) were dissolved in methanol (15 mL) under a nitrogenatmosphere. The resulting mixture was stirred for 3 h at 50-60° C. andthen NaCNBH₃ (0.052 g, 0.82 mmol) was added portion-wise at 0-10° C. Thereaction mixture was stirred for 2 h at room temperature, thenpartitioned between H₂O (15 mL) and EtOAc (25 mL). The aqueous layer wasfurther extracted with EtOAc (2×25 mL), the combined organic layers weredried (Na₂SO₄) and the solvent was removed in-vacuo. The residue waspurified using purification method A to give ethyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate,Example 1-1 (40 mg, 20%) as a gum.

The data for Example 1-1 are in Table 3.

Route B Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 1-2, ethyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate

Ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate,(Intermediate 1) (100 mg, 0.52 mmol), TEA (0.36 mL, 2.61 mmol),tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, (Intermediate 3)(117 mg, 0.52 mmol) and ZnCl₂ solution in diethyl ether (1 M₁ 0.02 mL,0.02 mmol) were dissolved in MeOH (10 mL) under nitrogen and stirred for4 h at 60° C.

NaCNBH₃ (98 mg, 1.57 mmol) was then added portion-wise at 0° C. and theresulting reaction mixture was stirred for 12 h at room temperature. Thereaction mixture was partitioned between H₂O (30 mL) and 10% MeOH in DCM(50 mL), and the aqueous layer was further extracted with 10% MeOH inDCM (2×50 mL). The combined organic layers were dried (Na₂SO₄), thesolvent was removed in-vacuo and the crude product was purified bycolumn chromatography (Neutral Alumina, 0-2% methanol in DCM) to givetert-butyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate(92 mg, 50%) as a gum. LCMS (System 1, Method C): m/z 351(M+H)+(ESI+ve), at 5.21 min, 202 nm.

tert-Butyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate(92 mg, 0.26 mmol), TEA (0.07 mL, 0.53 mmol) and diethylamine,(Intermediate 4) (0.081 mL, 0.79 mmol) were dissolved in toluene (10 mL)at 0° C. under nitrogen and the mixture was stirred for 20 min at roomtemperature. Trimethylaluminium solution in toluene (2 M, 0.39 mL, 0.79mmol) was added at 0° C. and the reaction mixture was then heated at 60°C. for 16 h. The reaction mixture was partitioned between ice-cold water(50 mL) and 10% MeOH in DCM (100 mL), and the aqueous layer was furtherextracted with 10% MeOH in DCM (2×100 mL). The combined organic layerswere washed with ammonium chloride solution, dried (Na₂SO₄) and thesolvent was removed in-vacuo to give crude tert-butyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate(108 mg, >100%) as a gum.

LCMS (System 1, Method C): m/z 378 (M+H)⁺ (ESI+ve), at 4.44 min, 210 nm.

tert-Butyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate(108 mg, 0.29 mmol) was dissolved in DCM (10 mL) and trifluoroaceticacid (0.22 mL, 2.86 mmol) was added at 0° C. The resulting reactionmixture was stirred at 25° C. for 16 h. The solvents were removedin-vacuo and the residue was purified by triturating with diethyl ether(3×30 mL) to give(1R,5S,6r)-3-(2-azaspiro[3.3]heptan-6-yl)-N,N-diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamidetrifluoroacetic acid salt (110 mg, 95%) as a gum.

LCMS (System 1, Method C): m/z 278 (M+H)⁺ (ESI+ve), at 0.30 min, 202 nm.

(1R,5S,6r)-3-(2-azaspiro[3.3]heptan-6-yl)-N,N-diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamidetrifluoroacetic acid salt (79 mg, 0.29 mmol) and TEA (0.12 mL, 0.86mmol) were dissolved in DCM (10 mL). Ethyl chloroformate, (Intermediate52) (0.04 mL, 0.43 mmol) was added at 0° C. and the reaction mixture wasstirred at room temperature for 16 h. The reaction mixture waspartitioned between ammonium chloride solution (50 mL) and 10% MeOH inDCM (100 mL) and the aqueous layer was further extracted with 10% MeOHin DCM (2×100 mL). The combined organic layers were dried (Na₂SO₄) andthe solvent was removed in-vacuo. The crude product was purified usingpurification method B to give ethyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate,Example 1-2 (13 mg, 9%) as a gum.

The data for Example 1-2 are in Table 3.

Route C Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 1-3, ethyl6-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azaspiro[3.3]heptane-2-carboxylate

Ethyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate,Example 1-1 (45 mg, 0.14 mmol), TEA (0.03 mL, 0.28 mmol) andN-ethylisopropylamine, (Intermediate 5) (0.05 mL, 0.42 mmol) weredissolved in toluene (10 mL) at 0° C. under nitrogen and the resultingmixture was stirred for 20 min at room temperature. Trimethylaluminiumsolution in toluene (2 M, 0.35 mL, 0.70 mmol) was added at 0° C. and thereaction mixture was heated at 60° C. for 16 h. The reaction mixture waspartitioned between ice-cold water (25 mL) and 10% MeOH in DCM (50 mL)and the aqueous layer was further extracted with 10% MeOH in DCM (2×50mL). The combined organic layers were washed with ammonium chloridesolution, dried (Na₂SO₄) and the solvent was removed in-vacuo. The crudeproduct was purified using purification method C to give ethyl6-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azaspiro[3.3]heptane-2-carboxylate,Example 1-3 (2 mg, 1%) as a gum.

The data for Example 1-3 are in Table 3.

Route D Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 1-4, ethyl6-[(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate

3-tert-Butyl 6-ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate, (Intermediate 6)(400 mg, 1.57 mmol) was dissolved in toluene (10 mL).N,O-Dimethylhydroxylamine hydrochloride, (Intermediate 7) (183 mg, 1.88mmol) and triethylamine (0.7 mL, 4.71 mmol) were added and the resultingmixture was stirred at 25° C. for 30 min. Trimethylaluminium solution intoluene (2 M, 3.1 mL, 6.27 mmol) was added dropwise at 0° C., and thereaction mixture was stirred at 40° C. for 2 h. The solvents wereremoved in-vacuo, the residue was partitioned between H₂O (120 mL) andEtOAc (100 mL) and the aqueous layer was further extracted with EtOAc(2×100 mL). The combined organic layers were dried (Na₂SO₄), the solventwas removed in-vacuo and the residue was purified by columnchromatography (Normal basic activated alumina, 0.5-1.0% MeOH in DCM) togive tert-butyl(1R,5S,6r)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(260 mg, 61%) as a gum.

LCMS (System 1, Method C): m/z 271 (M+H)⁺ (ESI+ve), at 3.82 min, 215 nm.

tert-Butyl(1R,5S,6r)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(260 mg, 0.96 mmol) was dissolved in THF (5 mL) and the solution wascooled down to 0° C. Methylmagnesium bromide solution in diethyl ether,(Intermediate 8) (3 M₁ 1.0 mL, 2.88 mmol) was added dropwise and theresulting reaction mixture was stirred at 0° C. for 1 h. The solventswere then removed in-vacuo, and the residue was partitioned between H₂O(100 mL) and EtOAc (80 mL). The aqueous layer was further extracted withEtOAc (2×80 mL), and the combined organic layers were dried (Na₂SO₄),and the solvents were removed in-vacuo to give crude tert-butyl(1R,5S,6r)-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate,(Intermediate 40) (190 mg, 88%) as a gum. The crude product was used inthe next step without further purification.

LCMS (System 1, Method C): m/z 170 (M+H-56)⁺ (ESI+ve), at 4.00 min, 202nm.

tert-Butyl (1R,5S,6r)-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(50 mg, 0.22 mmol) was dissolved in MeOH (3 mL). Phenyltrimethylammoniumtribromide (Intermediate 9) (83 mg, 0.22 mmol) was added and theresulting reaction mixture was stirred at 25° C. for 7 h and thenconcentrated in-vacuo to give crude tert-butyl(1R,5S,6r)-6-(bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (65mg, 97%) as a gum. The crude product was used in the next step withoutfurther workup or purification due to its instability.

LCMS (System 2, Method A): m/z 289/291 (M+H-16)⁺ (ESI+ve), at 2.30 min,202 nm.

tert-Butyl(1R,5S,6r)-6-(bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (65mg, 0.21 mmol) was dissolved in MeOH (3 mL), thioacetamide,(Intermediate 10) (32 mg, 0.43 mmol) was added and the resulting mixturewas stirred at 25° C. for 2 h. The solvents were removed in-vacuo andthe residue was partitioned between H₂O (40 mL) and EtOAc (30 mL). Theaqueous layer was further extracted with EtOAc (2×30 mL), the combinedorganic layers were dried (Na₂SO₄) and the solvents were removedin-vacuo. The residue was purified by column chromatography (Normalneutral activated alumina, 15-20% EtOAc in hexane) to give tert-butyl(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(21 mg, 34%) as a gum.

LCMS (System 1, Method C): m/z 281 (M+H)⁺ (ESI+ve), at 4.78 min, 251 nm.

tert-Butyl(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(20 mg, 0.07 mmol) was dissolved in DCM (1 mL) and trifluoroacetic acid(0.3 mL) was added dropwise. The resulting reaction mixture was stirredat 25° C. for 5 h and then the solvents were removed in-vacuo. Theresidue was purified by triturating with pentane (3×0.5 mL) to give(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexanetrifluoroacetic acid salt (12 mg, 92%) as a solid.

LCMS (System 1, Method C): m/z 181 (M+H)⁺ (ESI+ve), at 3.03 min, 220 nm.

(1R,5S,6r)-6-(2-Methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexanetrifluoroacetic acid salt (12 mg, 0.07 mmol), ethyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, (Intermediate 2) (14 mg,0.07 mmol), triethylamine (0.03 mL, 0.22 mmol) and ZnCl₂ (1 mg, 0.01mmol) were dissolved in MeOH (2 mL) and the resulting mixture wasstirred at 65° C. for 5 h. The mixture was cooled to 0° C. and NaBH₃CN(13 mg, 0.22 mmol) was added portion-wise. The resulting reactionmixture was stirred at 25° C. for 17 h and then the solvents wereremoved in-vacuo. The residue was partitioned between H₂O (30 mL) andEtOAc (20 mL) and the aqueous layer was further extracted with EtOAc(2×20 mL). The combined organic layers were dried (Na₂SO₄) and thesolvent was removed in-vacuo. The residue was purified usingpurification method D to give ethyl6-[(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate,Example 1-4 (4 mg, 17%) as a gum.

The data for Example 1-4 are in Table 3.

Route E Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 2-19, ethyl2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

Ethyl2-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-1 (150 mg, 0.45 mmol) was dissolved in THF (2 mL) and asolution of LiOH (32 mg, 1.34 mmol) in water (2 mL) was added at −20° C.The resulting mixture was stirred at room temperature for 5 h. Thereaction mixture was then acidified by the addition of conc. aq. HCl andthe solvents were removed in-vacuo to give(1R,5S,6r)-3-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-3-azabicyclo[0.1.0]hexane-6-carboxylicacid (115 mg, 84%) as a solid.

LCMS (System 2, Method D): m/z 309 (M+H)⁺ (ESI+ve), at 1.35 min, 202 nm.

(1R,5S,6r)-3-[6-(Ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (115 mg, 0.37 mmol) and HATU (212 mg, 0.56 mmol) were dissolved inDMF at 0° C. and DIPEA (0.19 mL, 1.12 mmol) was added. The resultingmixture was stirred at 0° C. for 1 h, then 4-azaspiro[2.3]hexane,(Intermediate 27) (35.0 mg, 0.41 mmol) was added at 0° C. and theresulting mixture was stirred at room temperature for 3 h. The reactionmixture was partitioned between cold H₂O (20 mL) and EtOAc (10 mL), andthe aqueous layer was further extracted with EtOAc (2×10 mL). Thecombined organic layers were dried (Na₂SO₄) and the solvent was removedin-vacuo to give the crude product, which was purified usingpurification method AD followed by purification method AE to give ethyl2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-19 Isomer 1 (18 mg, 12%) as a gum and ethyl2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-19 Isomer 2 (18 mg, 12%) as a gum.

The data for Example 2-19 Isomer 1 and Isomer 2 are in Table 3.

Route F Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 2-25, ethyl2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

tert-Butyl(1R,5S,6r)-6-propanoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate,(Intermediate 32) (160 mg, 0.67 mmol) was dissolved in DCM (3 mL) andtrifluoroacetic acid (1 mL) was added dropwise. The resulting reactionmixture was stirred at 25° C. for 5 h. The solvents were removedin-vacuo, and the residue was purified by triturating with pentane (3×1mL) to give 1-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]propan-1-onetrifluoroacetic acid salt (80 mg, 99%) as a gum.

LCMS (System 1, Method C): m/z 140 (M+H)⁺ (ESI+ve), at 2.76 min, 202 nm.

1-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]propan-1-one trifluoroaceticacid salt (80 mg, 0.57 mmol), ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (124 mg,0.63 mmol), triethylamine (0.1 mL, 1.72 mmol) and ZnCl₂ (7 mg, 0.06mmol) were dissolved in MeOH (10 mL) and the resulting mixture wasstirred at 65° C. for 5 h. The mixture was then cooled to 0° C. andNaBH₃CN (109 mg, 0.57 mmol) was added portion-wise. The reaction mixturewas stirred at 25° C. for 17 h, then the solvents were removed in-vacuo.The residue was partitioned between H₂O (100 mL) and EtOAc (80 mL), andthe aqueous layer was further extracted with EtOAc (2×80 mL). Thecombined organic layers were dried (Na₂SO₄), the solvent was removedin-vacuo, and the residue was purified by column chromatography (Normalneutral activated alumina, 50% EtOAc in hexane) to give ethyl2-[(1R,5S,6r)-6-propanoyl-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate(130 mg, 75%) as a gum.

LCMS (System 1, Method C): m/z 321 (M+H)⁺ (ESI+ve), at 4.23 min, 220 nm.

Ethyl2-[(1R,5S,6r)-6-propanoyl-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate(100 mg, 0.31 mmol) and sodium acetate (77 mg, 0.94 mmol) were dissolvedin ethanol (5 mL) and the resulting mixture was stirred at 25° C. for 30min. 0-Methylhydroxylamine hydrochloride, (Intermediate 33) (52 mg, 0.63mmol) was added and the reaction mixture was stirred at 25° C. for 17 h.The solvents were removed in-vacuo, and the residue was partitionedbetween H₂O (80 mL) and EtOAc (60 mL). The aqueous layer was furtherextracted with EtOAc (2×60 mL), the combined organic layers were dried(Na₂SO₄) and the solvent was removed in-vacuo. The residue was purifiedusing purification method AK to give ethyl2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-25 Isomer 1 (7 mg, 6%), ethyl2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-25 Isomer 2 (9 mg, 8%), ethyl2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-25 Isomer 3 (18 mg, 17%) and ethyl2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-25 Isomer 4 (17 mg, 16%), all as gums.

The data for Example 2-25 Isomer 2 and Isomer 4 are in Table 3.

Route G Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 2-27, ethyl2-{(1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl}-6-azaspiro[3.4]octane-6-carboxylate

tert-Butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate,(Intermediate 35) (100 mg, 0.51 mmol) was dissolved in THF (5 mL) andN-methyl-2-pyrrolidinone (150 mg, 1.52 mmol) and triethylamine (0.3 mL,2.02 mmol) were added. The resulting mixture was stirred at 70° C. for 1h, then 2,2,2-trifluoroethyl trifluoromethanesulfonate, (Intermediate36) (129 mg, 0.56 mmol) was added at 25° C. The resulting reactionmixture was stirred at 80° C. for 18 h, then the solvents were removedin-vacuo. The residue was partitioned between H₂O (80 mL) and EtOAc (60mL), and the aqueous layer was further extracted with EtOAc (2×60 mL).The combined organic layers were dried (Na₂SO₄), the solvents wereremoved in-vacuo and residue was purified by column chromatography(Normal neutral activated alumina, 2-5% MeOH in DCM) to give tert-butyl(1R,5S,6s)-6-[(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate(118 mg, 84%) as a gum.

LCMS (System 1, Method C): m/z 225 (M+H-56)⁺ (ESI+ve), at 4.61 min, 202nm.

tert-Butyl(1R,5S,6s)-6-[(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate(118 mg, 0.43 mmol) was dissolved in methanol (5 mL) and acetaldehyde,(Intermediate 37) (38 mg, 0.86 mmol), triethylamine (0.2 mL, 1.29 mmol)and ZnCl₂ (6 mg, 0.43 mmol) were added. The resulting mixture wasstirred at 40° C. for 7 h, then NaBH₃CN (81 mg, 1.29 mmol) was addedportion-wise. The reaction mixture was stirred at 25° C. for 17 h, thenthe solvents were removed in-vacuo. The residue was partitioned betweenH₂O (100 mL) and EtOAc (80 mL), and the aqueous layer was furtherextracted with EtOAc (2×80 mL). The combined organic layers were dried(Na2SO₄), the solvent was removed in-vacuo and the residue was purifiedby column chromatography (Normal basic activated alumina, 0.5-1.0% MeOHin DCM) to give tert-butyl(1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate(125 mg, 96%) as a gum.

LCMS (System 1, Method C): m/z 309 (M+H)⁺ (ESI+ve), at 5.58 min, 202 nm.

tert-Butyl(1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate(125 mg, 0.41 mmol) was dissolved in 1,4-dioxane (5 mL) and HCl solutionin 1,4-dioxane (4 M₁ 3 mL) was added dropwise. The resulting mixture wasstirred at 25° C. for 5 h, then the solvents were removed in-vacuo. Theresidue was purified by triturating with diethyl ether (3×3 mL) to give(1R,5S,6s)-N-ethyl-N-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-aminehydrochloride salt (100 mg, 100%) as a solid.

LCMS (System 2, Method A): m/z 209 (M+H)⁺ (ESI+ve), at 1.42 min, 202 nm.

(1R,5S,6s)-N-ethyl-N-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-aminehydrochloride salt (100 mg, 0.48 mmol), ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (95 mg,0.48 mmol), triethylamine (0.2 mL, 1.44 mmol) and ZnCl₂ (7 mg, 0.05mmol) were dissolved in MeOH (10 mL) and the resulting mixture wasstirred at 70° C. for 8 h. The mixture was cooled to 0° C. and NaBH3CN(91 mg, 1.44 mmol) was added portion-wise. The reaction mixture wasstirred at 25° C. for 17 h, then the solvents were removed in-vacuo, Theresidue was partitioned between H₂O (100 mL) and EtOAc (80 mL), and theaqueous layer was further extracted with EtOAc (2×80 mL). The combinedorganic layers were dried (Na₂SO₄), the solvent was removed in-vacuo,and the residue was purified using purification method AM to give ethyl2-{(1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-27 (53 mg, 33%) as a gum.

The data for Example 2-27 are in Table 3.

Route H Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 2-28, ethyl2-[(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

(1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-ol, (Intermediate 38) (110 mg,1.11 mmol) was dissolved in DCM (10 mL) and triethylamine (0.5 mL, 3.30mmol) was added. The mixture was stirred at 0° C. for 20 min, thendi-tert-butyl dicarbonate (362 mg, 1.66 mmol) was added at 0° C. Theresulting reaction mixture was stirred at 25° C. for 2 h, then thesolvents were removed in-vacuo. The residue was partitioned between H₂O(80 mL) and EtOAc (60 mL), and the aqueous layer was further extractedwith EtOAc (2×60 mL). The combined organic layers were dried (Na₂SO₄),the solvent was removed in-vacuo and the residue was purified bytriturating with pentane give tert-butyl(1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (180 mg,81%) as a liquid.

LCMS (System 1, Method C): m/z 144 (M+H-56)⁺ (ESI+ve), at 3.40 min, 210nm.

tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate(180 mg, 0.90 mmol) was dissolved in DMF (8 mL), cooled to 0° C. and NaH(60% in paraffin oil, 108 mg, 2.71 mmol) was added. The mixture wasstirred at 0° C. for 20 min, then (1-bromoethyl)benzene, (Intermediate39) (250 mg, 1.36 mmol) was added dropwise at 0° C.

The resulting reaction mixture was stirred at 25° C. for 5 h, then thesolvents were removed in-vacuo. The residue was partitioned between H₂O(100 mL) and EtOAc (60 mL), and the aqueous layer was further extractedwith EtOAc (2×60 mL). The combined organic layers were dried (Na₂SO₄),and the solvents were removed in-vacuo to give tert-butyl(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate(250 mg, 91%) as a liquid.

LCMS (System 1, Method C): m/z 248 (M+H-56)⁺ (ESI+ve), at 5.70 min, 210nm.

tert-Butyl(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate(250 mg, 0.83 mmol) was dissolved in DCM (10 mL) and cooled to 0° C.Trifluoroacetic acid (2 mL) was added dropwise and the resultingreaction mixture was stirred at 25° C. for 6 h. The solvents wereremoved in-vacuo, and the residue was purified by triturating withpentane (3×1 mL) to give(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hexane trifluoroaceticacid salt (160 mg, 96%) as a gum.

LCMS (System 1, Method C): m/z 204 (M+H)⁺ (ESI+ve), at 3.97 min, 210 nm.

(1R,5S,6s)-6-(1-Phenylethoxy)-3-azabicyclo[3.1.0]hexane trifluoroaceticacid salt (150 mg, 0.74 mmol), ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (145 mg,0.74 mmol), triethylamine (0.3 mL, 2.21 mmol) and ZnCl₂ (10 mg, 0.07mmol) were dissolved in MeOH (10 mL) and the resulting mixture wasstirred at 65° C. for 7 h. The mixture was cooled to 0° C. and NaBH3CN(139 mg, 2.21 mmol) was added portion-wise. The reaction mixture wasstirred at 25° C. for 17 h, the the solvents were removed in-vacuo. Theresidue was partitioned between H₂O (100 mL) and EtOAc (80 mL), and theaqueous layer was further extracted with EtOAc (2×80 mL). The combinedorganic layers were dried (Na₂SO₄), the solvent was removed in-vacuo,and the residue was purified using purification method AN to give ethyl2-[(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-28 Isomer 1 (8 mg, 3%) as a gum and ethyl2-[(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-28 Isomer 2 (7 mg, 3%) as a gum.

The data for Example 2-28 Isomer 1 and Isomer 2 are in Table 3.

Route I Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 2-29, ethyl2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

tert-Butyl (1R,5S,6r)-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate,(Intermediate 40) (200 mg, 0.89 mmol) was dissolved in DMF (10 mL) andN,N-dimethylformamide dimethyl acetal, (Intermediate 41) (211 mg, 1.78mmol) was added. The resulting mixture was stirred at 100° C. for 24 h,then methylhydrazine sulfate, (Intermediate 42) (269 mg, 1.86 mmol) wasadded at 25° C., and the mixture was stirred at 100° C. for 30 h. Thesolvents were removed in-vacuo, and the residue was partitioned betweenH₂O (150 mL) and EtOAc (100 mL). The aqueous layer was further extractedwith EtOAc (2×100 mL), the combined organic layers were dried (Na₂SO₄),and the solvents were removed in-vacuo. The residue was purified bycolumn chromatography (Normal basic activated alumina, 1-3% MeOH in DCM)to give a mixture of tert-butyl(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylateand tert-butyl(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(170 mg, 73%) as a liquid.

LCMS (System 1, Method C): m/z 264 (M+H)⁺ (ESI+ve), at 4.10 min, 202 nm.

A mixture of tert-butyl(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylateand tert-butyl(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(170 mg, 0.65 mmol) was dissolved in 1,4-dioxane (5 mL) and HCl solutionin 1,4-dioxane (4 M₁ 3 mL) was added dropwise. The resulting mixture wasstirred at 25° C. for 16 h, then the solvents were removed in-vacuo. Theresidue was purified by triturating with diethyl ether (3×5 mL) to givea mixture of(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexanehydrochloride salt and(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride salt (120 mg, 93%) as a gum.

LCMS (System 1, Method C): m/z 164 (M+H)⁺ (ESI+ve), at 2.53 min, 221 nm.

A mixture of(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexanehydrochloride salt and(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride salt (120 mg, 0.74 mmol), ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (160 mg,0.81 mmol), triethylamine (0.3 mL, 2.20 mmol) and ZnCl₂ (10 mg, 0.07mmol) were dissolved in MeOH (10 mL) and stirred together at 65° C. for8 h. The mixture was then cooled to 0° C., NaBH₃CN (140 mg, 2.20 mmol)was added portion-wise, and the resulting mixture was stirred at 25° C.for 17 h. The solvents were removed in-vacuo, and the residue waspartitioned between H₂O (100 mL) and EtOAc (80 mL). The aqueous layerwas further extracted with EtOAc (2×80 mL), the combined organic layerswere dried (Na₂SO₄), and the solvent was removed in-vacuo. The residuewas purified using purification method AO to give ethyl2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-29 Isomer 1 (9 mg, 4%), ethyl2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylateIsomer 1 (8 mg, 3%), ethyl2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-29 Isomer 2 (6 mg, 2%) and ethyl2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylateIsomer 2 (8 mg, 3%), all as gums.

The data for Example 2-29 Isomer 2 are in Table 3.

Route J Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 3-3, methyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate

3-tert-Butyl 6-ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate, (Intermediate 6)(200 mg, 0.78 mmol) and TEA (0.31 mL, 2.35 mmol) were dissolved intoluene and cooled to 0° C. Diethylamine, (Intermediate 4) (0.16 mL,1.57 mmol) was added, followed by trimethylaluminium solution in toluene(2 M, 0.8 mL, 1.57 mmol). The reaction mixture was heated at 60° C. for5 h, then diluted with water (150 mL) and extracted with EtOAc (3×60mL). The combined organic layers were dried (Na₂SO₄) and concentratedin-vacuo to give the crude product, which was purified by columnchromatography (Normal neutral activated alumina, 0-30% EtOAc in hexane)to give tert-butyl(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(130 mg, 59%) as a gum.

LCMS (System 1, Method C): m/z 283 (M+H)⁺ (ESI+ve), at 4.22 min, 210 nm.

tert-Butyl(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(125 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL) and cooledto 0° C. TFA (2.5 mL) was added and the resulting mixture was allowed tostir at room temperature for 3 h. The mixture was then diluted withtoluene (2.5 mL) and concentrated in-vacuo to give the crude(1R,5S,6r)-N,N-diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamidetrifluoroacetic acid salt (125 mg, 100%) as a gum, which was used in thenext step without further purification.

LCMS (System 1, Method C): m/z 183 (M+H)⁺ (ESI+ve), at 2.60 min, 215 nm.

(1R,5S,6r)-N,N-Diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamidetrifluoroacetic acid salt (125 mg, 0.68 mmol), methyl6-oxo-2-azaspiro[3.4]octane-2-carboxylate, (Intermediate 46) (125 mg,1.31 mmol) and TEA (0.47 mL, 3.41 mmol) were dissolved in methanol (10mL).

The mixture was degassed for 30 min under nitrogen, ZnCl₂ solution indiethyl ether (1 M₁ 0.03 mL, 0.03 mmol) was added, and the mixture wasstirred at 60° C. for 3 h. The mixture was cooled to 0° C. and NaCNBH₃(129 mg, 2.04 mmol) was added portion-wise. The reaction mixture wasthen stirred at room temperature for 5 h, diluted with water (150 mL)and extracted with EtOAc (3×60 mL). The combined organic layers weredried (Na₂SO₄) and concentrated in-vacuo. The residue was purified usingpurification method AS to give methyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate,Example 3-3 Isomer 1 (20 mg, 8%) as a gum and methyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate,Example 3-3 Isomer 2 (18 mg, 8%) as a gum.

The data for Example 3-3 Isomer 1 and Isomer 2 are in Table 3.

Route J Typical Procedure for the Preparation of Amines as Exemplifiedby the Preparation of Example 7-5, ethyl3-[(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate

3-tert-Butyl 6-ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate, (Intermediate 6)(650 mg, 2.55 mmol) was dissolved in THF (10 mL) and cooled to 0° C.LiBH₄ solution in THF (3 M₁ 3.4 mL, 10.2 mmol) was added and the mixturewas stirred at room temperature for 16 h. The mixture was diluted withwater (150 mL) and extracted with EtOAc (3×60 mL). The combined organiclayers were dried (Na₂SO₄), concentrated in-vacuo and the residue waspurified by column chromatography (Normal phase, neutral silica gel,60-120 mesh, 0-30% EtOAc in hexane) to give tert-butyl(1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(400 mg, 74%) as a liquid.

LCMS (System 1, Method C): m/z 214 (M+H)⁺ (ESI+ve), at 3.37 min, 210 nm.

tert-Butyl(1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(230 mg, 1.08 mmol) was dissolved in dichloromethane (10 mL) and cooledto 0° C. Dess-Martin periodinane, (Intermediate 48) (503 mg, 1.19 mmol)was added portion-wise and the reaction mixture was stirred at roomtemperature for 6 h. The reaction mixture was quenched with a saturatedaqueous solution of NaHCO₃, then diluted with water (100 mL) andextracted with EtOAc (3×40 mL). The combined organic layers were dried(Na₂SO₄) and concentrated in-vacuo to give the crude tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (240 mg,100%) as a liquid, which was used in the next step without furtherpurification.

LCMS (System 1, Method C): m/z 156 (M+H-56)⁺ (ESI+ve), at 3.97 min, 210nm.

tert-Butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(230 mg, 1.10 mmol) was dissolved in methanol (10 mL). Ethylaminesolution in THF, (Intermediate 49) (2 M, 2.7 mL, 5.45 mmol) was added,followed by ZnCl₂ solution in diethyl ether (1 M, 0.05 mL, 0.05 mmol).The resulting mixture was stirred at 60° C. for 6 h, then cooled to 0°C. and NaCNBH₃ (202 mg, 2.13 mmol) was added. The mixture was stirred atroom temperature for 16 h, then concentrated in-vacuo. The residue wasdiluted with water (160 mL) and extracted with EtOAc (3×50 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated in-vacuo togive the crude tert-butyl(1R,5S,6r)-6-[(ethylamino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 77%) as a liquid, which was used in the next step withoutfurther purification.

LCMS (System 1, Method E): m/z 241 (M+H)⁺ (ESI+ve), at 3.78 min, 210 nm.

tert-Butyl(1R,5S,6r)-6-[(ethylamino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(20 mg, 0.83 mmol) was dissolved in dichloromethane (10 mL) and cooledto 0° C. TEA (0.3 mL, 2.49 mmol) was added, followed by acetyl chloride,(Intermediate 50) (130 mg, 1.66 mmol). The reaction mixture was stirredat 0° C. for 2 h, then diluted with water (150 mL) and extracted withEtOAc (3×40 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in-vacuo. The residue was purified by column chromatography(Normal phase, neutral alumina, 0-2% MeOH in DCM) to give tert-butyl(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(130 mg, 55%) as a liquid.

LCMS (System 1, Method E): m/z 227 (M+H-56)⁺ (ESI+ve), at 4.18 min, 202nm.

tert-Butyl(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(120 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL) and cooledto 0° C. TFA (2.5 mL) was added and the reaction mixture was stirred atroom temperature for 2 h. The mixture was diluted with toluene (2.5 mL)and concentrated in-vacuo to give the crudeN-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl]-N-ethylacetamidetrifluoroacetic acid salt (120 mg, 100%) as a gum, which was used in thenext step without further purification.

LCMS (System 1, Method E): m/z 183 (M+H)⁺ (ESI+ve), at 2.31 min, 202 nm.

N-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl]-N-ethylacetamidetrifluoroacetic acid salt (103 mg, 0.57 mmol) and TEA (0.4 mL, 2.83mmol) were dissolved in MeOH (5 mL). Ethyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate, (Intermediate 47) (122mg, 0.62 mmol) was added, followed by ZnCl₂ solution in diethyl ether (1M₁ 0.3 mL, 0.28 mmol). The resulting mixture was stirred at 60° C. for 5h, then cooled to 0° C. and NaCNBH₃ (105 mg, 1.69 mmol) was added. Themixture was stirred at 60° C. for 12 h, then diluted with water (150 mL)and extracted with EtOAc (3×40 mL). The combined organic layers weredried (Na₂SO₄) and concentrated in-vacuo and the residue was purifiedusing purification method BE to give ethyl3-[(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 4-5 Isomer 1 (52 mg, 25%) as a gum and ethyl3-[(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,Example 4-5 Isomer 2 (21 mg, 10%) as a gum.

The data for Example 4-5 Isomer 2 are in Table 3.

TABLE 2 Intermediates Intermediate Synthetic Intermediates Number NameRoute Used Data 1 Ethyl (1R,5S,6r)-3- — — Commercially available,azabicyclo[3.1.0]hexane-6- CAS: 174456-77-0 carboxylate 2 Ethyl6-oxo-2-azaspiro[3.3]heptane-2- — — See WO2016147011 carboxylate 3tert-Butyl 6-oxo-2- — — Commercially available,azaspiro[3.3]heptane-2-carboxylate CAS: 1181816-12-5 4 Diethylamine — —Commercially available, CAS: 109-89-7 5 N-Ethylisopropylamine — —Commercially available, CAS: 19961-27-4 6 3-tert-Butyl 6-ethyl(1R,5S,6r)-3- — — Commercially available, azabicyclo[3.1.0]hexane-3,6-CAS: 134575-37-4 dicarboxylate 7 N,O-Dimethylhydroxylamine — —Commercially available, hydrochloride CAS: 6638-79-5 8 Methylmagnesiumbromide — — Commercially available, CAS: 75-16-1 9Phenyltrimethylammonium tribromide — — Commercially available, CAS:4207-56-1 10 Thioacetamide — — Commercially available, CAS: 62-55-5 11Ethyl 2-oxo-6-azaspiro[3.4]octane-6- — — See WO2015118342 carboxylate 12Isobutylamine — — Commercially available, CAS: 78-81-9 13Cyclobutylmethylamine hydrochloride — — Commercially available, CAS:5454-82-0 14 1-Methylcyclobutylamine — — Commercially available, CAS:40571-47-9 15 N-Methylethylamine — — Commercially available, CAS:624-78-2 16 Methyl 2-oxo-6-azaspiro[3.4]octane-6- — — See WO2015118342carboxylate 17 Methyl 2-[(1R,5S,6r)-6- A  1 and 16 LCMS (System 1,Method C): (ethoxycarbonyl)-3- m/z 323 (M + H)⁺ (ES⁺), at 4.33azabicyclo[3.1.0]hex-3-yl]-6- min, 202 nmazaspiro[3.4]octane-6-carboxylate 18 N-Methylpropan-2-amine — —Commercially available, CAS: 4747-21-1 19 N-Ethylcyclopropanamine — —Commercially available, CAS: 26389-72-0 20 Pyrrolidine — — Commerciallyavailable, CAS: 123-75-1 21 Piperidine — — Commercially available, CAS:98-77-1 22 (2R)-2-Methylpiperidine — — Commercially available, CAS:1722-95-8 23 (2S)-2-Methylpiperidine — — Commercially available, CAS:3197-42-0 24 Azepane — — Commercially available, CAS: 111-49-9 251,4-Oxazepane — — Commercially available, CAS: 5638-60-8 262-Azaspiro[3.3]heptane hydrochloride — — Commercially available, CAS:1420271-08-4 27 4-Azaspiro[2.3]hexane — — Commercially available, CAS:125441-13-6 28 1-Azaspiro[3.3]heptane — — Commercially available,hydrochloride CAS: 1986337-29-4 29 6-Oxa-1-azaspiro[3.3]heptane — —Commercially available, hemioxalate CAS: 1380571-72-1 30N-Methoxyethanamine — — Commercially available, CAS: 1195657-97-6 31Ethylmagnesium bromide — — Commercially available, CAS: 925-90-6 32tert-Butyl (1R,5S,6r)-6-propanoyl-3- D 6, 7 and 31  LCMS (System 2,Method A): azabicyclo[3.1.0]hexane-3- (first two m/z 184 (M + H-56)⁺(ES⁺), at 2.16 carboxylate steps) min, 202 nm 33 O-Methylhydroxylamine —— Commercially available, hydrochloride CAS: 593-56-6 346-(Trifluoromethyl)-3- — — Commercially available,azabicyclo[3.1.0]hexane CAS: 1311314-49-4 hydrochloride 35 tert-Butyl(1R,5S,6s)-6-amino-3- — — Commercially available,azabicyclo[3.1.0]hexane-3- CAS: 273206-92-1 carboxylate 362,2,2-Trifluoroethyl — — Commercially available,trifluoromethanesulfonate CAS: 6226-25-1 37 Acetaldehyde — —Commercially available, CAS: 75-07-0 38(1R,5S,6s)-3-Azabicyclo[3.1.0]hexan- — — Commercially available, 6-olCAS: 1524707-84-3 39 (1-Bromoethyl)benzene — — Commercially available,CAS: 585-71-7 40 tert-Butyl (1R,5S,6r)-6-acetyl-3- D 6, 7 and 8  LCMS(System 1, Method C): azabicyclo[3.1.0]hexane-3- (first two m/z 170 (M +H-56)⁺ (ESI +ve), at carboxylate steps) 4.00 min, 202 nm 41N,N-Dimethylformamide dimethyl — — Commercially available, acetal CAS:4637-24-5 42 Methylhydrazine sulfate — — Commercially available, CAS:302-15-8 43 Ethyl 6-oxo-2-azaspiro[3.4]octane-2- — — See WO2016147011carboxylate 44 tert-Butyl 6-oxo-2-azaspiro [3.4] — — Commerciallyavailable, octane-2-carboxylate CAS: 1363382-39-1 45 Methylchloroformate — — Commercially available, CAS: 79-22-1 46 Methyl6-oxo-2-azaspiro[3.4]octane-2- 1 44 and 45 LCMS (System 1, Method E):carboxylate m/z 184 (M + H)⁺ (ES⁺), at 2.47 min, 202 nm 47 Ethyl3-oxo-8- — — Commercially available,azabicyclo[3.2.1]octane-8-carboxylate CAS: 32499-64-2 48 Dess-Martinperiodinane — — Commercially available, CAS: 87413-09-0 49 Ethylamine —— Commercially available, CAS: 75-04-7 50 Acetyl chloride — —Commercially available, CAS: 75-36-5 51 tert-Butyl 5-oxo-2- — —Commercially available, azabicyclo[2.2.2]octane-2-carboxylate CAS:617714-22-4 52 Ethyl chloroformate — — Commercially available, CAS:541-41-3 53 Ethyl 5-oxo-2- 2 51 and 52 LCMS (System 2, Method A):azabicyclo[2.2.2]octane-2-carboxylate m/z 198 (M + H)⁺ (ES⁺), at 1.64min, 229 nm 54 tert-Butyl (1S,4S)-5-oxo-2- — — Commercially available,azabicyclo[2.2.2]octane-2-carboxylate CAS: 1932043-29-2 55 Ethyl(1S,4S)-5-oxo-2- 2 54 and 52 LCMS (System 6, Method H):azabicyclo[2.2.2]octane-2-carboxylate m/z 198 (M + H)⁺ (ES⁺), at 0.83min, 230-400 nm 56 Ethyl (1S,4S)-5-[(1R,5S,6r)-6- A  1 and 55 LCMS(System 5, Method F): (ethoxycarbonyl)-3- m/z 337 (M + H)⁺ (ES⁺), at2.34 azabicyclo[3.1.0]hexan-3-yl]-2- min, 230-400 nmazabicyclo[2.2.2]octane-2-carboxylate 57 tert-Butyl (1R,4R)-5-oxo-2- — —Commercially available, azabicyclo[2.2.2]octane-2-carboxylate CAS:1818843-13-8 58 Ethyl (1R,4R)-5-oxo-2- 2 57 and 52 LCMS (System 6,Method H): azabicyclo[2.2.2]octane-2-carboxylate m/z 198 (M + H)⁺ (ES⁺),at 0.83 min, 190-400 nm 59 Ethyl (1R,4R)-5-[(1R,5S,6r)-6- A  1 and 58LCMS (System 6, Method H): (ethoxycarbonyl)-3- m/z 337 (M + H)⁺ (ES⁺),at 1.55 azabicyclo[3.1.0]hex-3-yl]-2- min, 190-400 nmazabicyclo[2.2.2]octane-2-carboxylate 60 Methyl 5-oxo-2- 1 51 and 45LCMS (System 2, Method D): azabicyclo[2.2.2]octane-2-carboxylate m/z 184(M + H)⁺ (ES⁺), at 1.39 min, 202 nm 61 Methyl 5-[(1R,5S,6r)-6- A  1 and60 LCMS (System 1, Method C): (ethoxycarbonyl)-3- m/z 323 (M + H)⁺(ES⁺), at 4.88 azabicyclo[3.1.0]hex-3-yl]-2- min, 220 nmazabicyclo[2.2.2]octane-2-carboxylate 62 tert-Butyl 3-oxo-9- — —Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 512822-27-4carboxylate 63 Ethyl 3-oxo-9- 1 62 and 52 LCMS (System 1, Method C):azabicyclo[3.3.1]nonane-9- m/z 212 (M + H)⁺(ES⁺), at 3.51 carboxylatemin, 202 nm 64 Ethyl 3-[(1R,5S,6r]-6- A  1 and 63 LCMS (System 1, MethodE): (ethoxycarbonyl)-3- m/z 351 (M + H)⁺ (ES⁺), at 5.30azabicyclo[3.1.0]hexan-3-yl]-9- and 5.39 min, 202 nmazabicyclo[3.3.1]nonane-9- carboxylate 65 Methyl 3-oxo-9- 2 62 and 45LCMS (System 1, Method E): azabicyclo[3.3.1]nonane-9- m/z 198 (M + H)⁺(ES⁺), at 3.34 carboxylate min, 215 nm 66 Methyl 3-[(1R,5S,6r)-6- A  1and 65 LCMS (System 1, Method E): (ethoxycarbonyl)-3- m/z 337 (M + H)⁺(ES⁺), at 4.99 azabicyclo[3.1.0]hexan-3-yl]-9- and 5.03 min, 202 nmazabicyclo[3.3.1]nonane-9- carboxylate 67 tert-Butyl 7-oxo-3-oxa-9- — —Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 280761-97-9carboxylate 68 Ethyl 7-oxo-3-oxa-9- 1 67 and 52 LCMS (System 2, MethodA): azabicyclo[3.3.1]nonane-9- m/z 214 (M + H)⁺ (ES⁺), at 1.53carboxylate min, 202 nm 69 Ethyl 7-[(1R,5S,6r)-6- A  1 and 68 LCMS(System 1, Method C): (ethoxycarbonyl)-3- m/z 353 (M + H)⁺ (ES⁺), at4.10 azabicyclo[3.1.0]hexan-3-yl]-3-oxa-9- min, 202 nmazabicyclo[3.3.1]nonane-9- carboxylate 70 Methyl 7-oxo-3-oxa-9- 1 67 and45 LCMS (System 2, Method D): azabicyclo[3.3.1]nonane-9- m/z 200 (M +H)⁺ (ES⁺), at 1.28 carboxylate min, 222 nm 71 Methyl 7-[(1R,5S,6r)-6- A 1 and 70 LCMS (System 1, Method C): (ethoxycarbonyl)-3- m/z 339 (M +H)⁺ (ES⁺), at 3.75 azabicyclo[3.1.0]hexan-3-yl]-3-oxa-9- min, 202 nmazabicyclo[3.3.1]nonane-9- carboxylate 72 Ethyl4-oxopiperidine-1-carboxylate — — Commercially available, CAS:29976-53-2 73 Ethyl (1R,5S,6r)-3-[1- A  1 and 72 LCMS (System 3, MethodE): (ethoxycarbonyl)piperidin-4-yl]-3- m/z 311 (M + H)⁺ (ES⁺), at 3.92azabicyclo[3.1.0]hexane-6- min, 202 nm carboxylate 74 tert-Butyl6-oxo-3- — — Commercially available, azabicyclo[3.1.1]heptane-3- CAS:1251013-26-9 carboxylate 75 Ethyl 6-oxo-3- 1 74 and 52 LCMS (System 4,Method B): azabicyclo[3.1.1]heptane-3- m/z 184 (M + H)⁺ (ES⁺), at 4.12carboxylate min, 202 nm 76 tert-Butyl 8-oxo-3- — — Commerciallyavailable, azabicyclo[3.2.1]octane-3-carboxylate CAS: 637301-19-0 77Ethyl 8-oxo-3- 1 76 and 52 LCMS (System 2, Method D):azabicyclo[3.2.1]octane-3-carboxylate m/z 198 (M + H)⁺ (ES⁺), at 1.48min, 202 nm 78 Ethyl 8-[(1R,5S,6r)-6- A  1 and 77 LCMS (System 3, MethodE): (ethoxycarbonyl)-3- m/z 337 (M + H)⁺ (ES⁺), at 5.07azabicyclo[3.1.0]hexan-3-yl]-3- min, 202 nmazabicyclo[3.2.1]octane-3-carboxylate 79 N-Methylcyclopropanamine — —Commercially available, CAS: 5163-20-2 80 Morpholine — — Commerciallyavailable, CAS: 110-91-8 81 Ethyl 4-oxoazepane-1-carboxylate — —Commercially available, CAS: 56515-89-0 82 Ethyl (1R,5S,6r)-3-(1- A  1and 81 LCMS (System 3, Method E): (ethoxycarbonyl)azepan-4-yl)-3- m/z325 (M + H)⁺ (ES⁺), at 4.18 azabicyclo[3.1.0]hexane-6- min, 202 nmcarboxylate 83 tert-Butyl 3-oxo-6- — — Commercially available,azabicyclo[3.2.1]octane-6-carboxylate CAS: 359779-74-1 84 Ethyl 3-oxo-6-1 83 and 52 LCMS (System 4, Method B):azabicyclo[3.2.1]octane-6-carboxylate m/z 198 (M + H)⁺(ES⁺), at 4.39min, 202 nm 85 Ethyl 3-[(1R,5S,6r)-6- A  1 and 84 LCMS (System 3, MethodE): (ethoxycarbonyl)-3- m/z 337 (M + H)⁺ (ES⁺), at 3.83azabicyclo[3.1.0]hexan-3-yl]-6- and 4.71 min, 202 nmazabicyclo[3.2.1]octane-6-carboxylate 86 tert-Butyl 5- — — Commerciallyavailable, oxohexahydrocyclopenta[c]pyrrole- CAS: 148404-28-82(1H)-carboxylate 87 Ethyl 5- 1 86 and 52 ¹H NMR (400 MHz, DMSO-d₆) δ:oxohexahydrocyclopenta[c]pyrrole- 1.19 (t, J = 7.25 Hz, 3 H), 2.05-2(1H)-carboxylate 2.16 (m, 2 H), 2.36-2.47 (m, 2 H), 2.84-2.96 (m, 2 H),3.12- 3.21 (m, 2 H), 3.53-3.63 (m, 2 H), 4.02-4.08 (m, 2 H). 88 ethyl5-((1R,5S)-6-(ethoxycarbonyl)-3- A  1 and 87 LCMS (System 3, Method E):azabicyclo[3.1.0]hexan-3- m/z 337 (M + H)⁺ (ES⁺), at 4.09yl)hexahydrocyclopenta[c]pyrrole- min, 202 nm 2(1H)-carboxylate

TABLE 3 Synthetic LCMS Method and System Ex. Intermediates Purificationand No. Name Used Method ¹H NMR Method LCMS data 1-1 Ethyl6-[(1R,5S,6r)-6- A A (400 MHz, DMSO-d₆) δ: 1.09-1.22 (m, 6H), 1.79 (s, 1H), 1.86-1.90 1 m/z 323 (ethoxycarbonyl)-3- 1 and 2 (m, 2 H), 1.90-1.99(m, 2 H), 2.12-2.21 (m, 2 H), 2.24 (d, J = 8.6 Hz, C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-2- 2 H), 2.81-2.84 (m, 1 H), 2.92 (d, J = 9.0Hz, 2 H), 3.73-3.83 (m, 2 H), (ES⁺), at azaspiro[3.3]heptane-2-3.83-3.91 (m, 2 H), 3.93-4.07 (m, 4 H). 4.36 min, carboxylate 202 nm 1-2Ethyl 6-[(1R,5S,6r)-6- B B (400 MHz, METHANOL-d₄) δ: 1.09 (t, J = 7.0Hz, 3 H), 1.16-1.32 (m, 4 m/z 350 (diethylcarbamoyl)-3- 1, 3, 6H),1.86-1.90 (m, 2 H), 2.02-2.15 (m, 2 H), 2.18-2.23 (m, 1 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-2- 4 and 52 2.24-2.34 (m, 2 H), 2.42 (d, J =9.2 Hz, 2 H), 2.94 (quin, J = 7.7 Hz, 1 H), (ES⁺), atazaspiro[3.3]heptane-2- 3.02 (d, J = 9.2 Hz, 2 H), 3.36 (q, J = 7.2 Hz,2 H), 3.53 (q, J = 7.0 Hz, 3.46 min, carboxylate 2 H), 3.84-3.91 (m, 2H), 3.95-4.01 (m, 2 H), 4.06 (q, J = 7.0 Hz, 2 H). 210 nm 1-3 Ethyl6-{(1R,5S,6r)-6- C C (400 MHz, METHANOL-d₄) δ: 1.07-1.17 (m, 3 H), 1.221 m/z 364 [ethyl(propan-2-yl)carbamoyl]- Example 1-1 (t, J = 7.2 Hz, 3H), 1.25-1.32 (m, 6H), 1.89-1.95 (m, 2 H), 2.02-2.14 (m, 2 H), C (M +H)⁺ 3-azabicyclo[3.1.0]hex-3-yl}-2- and 5 2.16-2.21 (m, 0.7H), 2.23-2.34(m, 2.3H), 2.37-2.48 (m, 2 H), (ES⁺), at azaspiro[3.3]heptane-2-2.88-2.98 (m, 1 H), 2.99-3.08 (m, 2 H), 3.22-3.29 (m, 1 H), 3.41- 4.07min, carboxylate 3.51 (m, 1 H), 3.83-3.91 (m, 2 H), 3.92-4.01 (m, 2 H),4.06 (q, 202 nm J = 7.09 Hz, 2 H), 4.41-4.49 (m, 0.3H), 4.57-4.69 (m,0.7H). 1-4 Ethyl 6-[(1R,5S,6r)-6- D D (400 MHz, METHANOL-d₄) δ: 1.22 (t,J = 7.0 Hz, 3 H), 1.80-1.87 (m, 4 m/z 348 (2-methyl-1,3-thiazol-4-yl)-3-6, 7, 8, 9, 2 H), 2.04-2.15 (m, 2 H), 2.22-2.37 (m, 4 H), 2.43 (d, J =8.9 Hz, 2 H), C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-2- 10 and 2 2.63 (s,3 H), 2.93 (quin, J = 7.6 Hz, 1 H), 3.07 (d, J = 9.2 Hz, 2 H), (ES⁺), atazaspiro[3.3]heptane-2- 3.85-3.91 (m, 2 H), 3.93-4.01 (m, 2 H), 4.06 (q,J = 7.0 Hz, 2 H). 4.08 min, carboxylate 210 nm 2-1 Mixture of isomers:ethyl A E (400 MHz, DMSO-d₆) δ: 1.17 (dt, J = 7.0, 3.5 Hz, 6H), 1 m/z337 2-[(1R,5S,6r)-6- 1 and 11 1.73-2.03 (m, 8 H), 2.24-2.27 m, 2 H),2.88-3.02 (m, 3 H), 3.10-3.30 (m, 5 H), C (M + H)⁺ (ethoxycarbonyl)-3-3.95-4.08 (m, 4 H). (ES⁺), at azabicyclo[3.1.0]hex-3-yl]-6- 4.65 min,azaspiro[3.4]octane-6- 202 nm carboxylate 2-2 Isomer 1: ethyl2-{(1R,5S,6r)-6- C F (400 MHz, METHANOL-d₄) δ: 0.92 (d, J = 6.6 Hz, 6H),1.14-1.36 (m, 1 m/z 364 [(2-methylpropyl)carbamoyl]-3- Example 2-1 4 H),1.72-1.81 (m, 1 H), 1.83-1.97 (m, 7 H), 2.08 (t, J = 9.0 Hz, 2 H), C(M + H)⁺ azabicyclo[3.1.0]hex-3-yl}-6- and 12 2.44 (d, J = 9.0 Hz, 2 H),2.87-3.13 (m, 4 H), 3.35-3.43 (m, 4 H), (ES⁺), at azaspiro[3.4]octane-6-4.12 (q, J = 7.1 Hz, 2 H). One exchangeable proton not observed. 3.91min, carboxylate 202 nm 2-2 Isomer 2: ethyl 2-{(1R,5S,6r)-6- C F (400MHz, METHANOL-d₄) δ: 0.93 (d, J = 6.4 Hz, 6H), 1.23-1.35 (m, 1 m/z 364[(2-methylpropyl)carbamoyl]-3- Example 2-1 4 H), 1.70-1.84 (m, 1 H),1.84-2.02 (m, 8 H), 2.02-2.15 (m, 2 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-6- and 12 2.34-2.51 (m, 2 H), 2.93-3.10 (m, 4H), 3.38-3.45 (m, 3 H), 4.06- (ES⁺), at azaspiro[3.4]octane-6- 4.17 (m,2 H). One exchangeable proton not observed. 3.96 min, carboxylate 202 nm2-3 Isomer 1: ethyl 2-{(1R,5S,6r)-6- C G (400 MHz, METHANOL-d₄) δ: 1.27(t, J = 6.8 Hz, 3 H), 1.63-1.79 (m, 1 m/z 376[(cyclobutylmethyl)carbamoyl]- Example 2-1 2 H), 1.80-1.99 (m, 9 H),1.99-2.19 (m, 4 H), 2.35-2.57 (m, 3 H), C (M + H)⁺3-azabicyclo[3.1.0]hex-3-yl}-6- and 13 2.93-3.13 (m, 4 H), 3.19 (d, J =7.1 Hz, 2 H), 3.36-3.46 (m, 3 H), (ES⁺), at azaspiro[3.4]octane-6- 4.12(q, J = 6.9 Hz, 2 H). One exchangeable proton not observed. 4.02 min,carboxylate 202 nm 2-3 Isomer 2: ethyl 2-{(1R,5S,6r)-6- C G (400 MHz,METHANOL-d₄) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.63-1.80 (m, 1 m/z 376[(cyclobutylmethyl)carbamoyl]- Example 2-1 2 H), 1.80-2.00 (m, 9 H),2.00-2.14 (m, 4 H), 2.33-2.56 (m, 3 H), C (M + H)⁺3-azabicyclo[3.1.0]hex-3-yl}-6- and 13 2.95-3.16 (m, 4 H), 3.20 (d, J =7.1 Hz, 2 H), 3.36-3.46 (m, 3 H), (ES⁺), at azaspiro[3.4]octane-6- 4.11(q, J = 7.0 Hz, 2 H). One exchangeable proton not observed. 4.04 min,carboxylate 202 nm 2-4 Isomer 1: ethyl 2-{(1R,5S,6r)-6- C H (400 MHz,METHANOL-d₄) δ: 1.21-1.33 (m, 3 H), 1.43 (s, 3 H), 1.80- 1 m/z 376[(1-methylcyclobutyl)carbamoyl]- Example 2-1 2.11 (m, 14H), 2.19-2.36(m, 2 H), 2.42 (d, J = 9.2 Hz, 2 H), 2.86- C (M + H)⁺3-azabicyclo[3.1.0]hex-3-yl}-6- and 14 3.15 (m, 3 H), 3.36 (d, J = 5.8Hz, 3 H), 4.12 (q, J = 7.0 Hz, 2 H). One (ES⁺), atazaspiro[3.4]octane-6- exchangeable proton not observed. 3.96 min,carboxylate 202 nm 2-4 Isomer 2: ethyl 2-{(1R,5S,6r)-6- C H (400 MHz,METHANOL-d₄) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.43 (s, 3 H), 1 m/z 376[(1-methylcyclobutyl)carbamoyl]- Example 2-1 1.72-1.97 (m, 10 H),1.97-2.18 (m, 4 H), 2.22-2.35 (m, 2 H), 2.35- C (M + H)⁺3-azabicyclo[3.1.0]hex-3-yl}-6- and 14 2.52 (m, 2 H), 2.94-3.13 (m, 3H), 3.35-3.47 (m, 3 H), 4.11 (q, (ES⁺), at azaspiro[3.4]octane-6- J =7.0 Hz, 2 H). One exchangeable proton not observed. 4.00 min,carboxylate 202 nm 2-5 Isomer 1: ethyl 2-{(1R,5S,6r)-6- C I then J (400MHz, METHANOL-d₄) δ: 1.10 (t, J = 7.3 Hz, 1 H), 1.18-1.41 (m, 5 H), 3m/z 350 [ethyl(methyl)carbamoyl]-3- Example 2-1 1.74-2.02 (m, 7 H),2.02-2.19 (m, 2 H), 2.27-2.29 (m, 1 H), E (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-6- and 15 2.45 (t, J = 7.3 Hz, 2 H), 2.93 (s,2 H), 3.06 (d, J = 9.8 Hz, 3 H), 3.19 (s, (ES⁺), atazaspiro[3.4]octane-6- 1 H), 3.35-3.51 (m, 4 H), 3.59 (q, J = 7.3 Hz, 1H), 4.12 (q, J = 7.1 Hz, 3.08 min, carboxylate 2 H). 215 nm 2-5 Isomer2: ethyl 2-{(1R,5S,6r)-6- C I then J (400 MHz, METHANOL-d₄) δ: 1.10 (t,J = 7.0 Hz, 1 H), 1.26 (t, J = 7.3 3 m/z 350 [ethyl(methyl)carbamoyl]-3-Example 2-1 Hz, 5 H), 1.78-2.02 (m, 7 H), 2.02-2.15 (m, 2 H), 2.27-2.29(m, 1 H), E (M + H)⁺ azabicyclo[3.1.0]hex-3-yl}-6- and 15 2.37-2.55 (m,2 H), 2.93 (s, 1 H), 3.00-3.14 (m, 3 H), 3.19 (s, 1 H), (ES⁺), atazaspiro[3.4]octane-6- 3.24-3.30 (m, 2 H), 3.35-3.48 (m, 3 H), 3.59 (q,J = 6.7 Hz, 1 H), 3.12 min, carboxylate 4.11 (q, J = 6.7 Hz, 2 H). 215nm 2-6 Isomer 1: ethyl 2-[(1R,5S,6r)-6- C K (400 MHz, METHANOL-d₄) δ:1.12 (t, J = 7.1 Hz, 3 H), 1.22-1.42 (m, 4 m/z 364 (diethylcarbamoyl)-3-Example 2-1 8 H), 1.87-2.03 (m, 2 H), 2.17-2.33 (m, 5 H), 2.34-2.47 (m,2 H), C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-6- and 4 3.35-3.47 (m, 6H),3.52-3.61 (m, 2 H), 3.80 (d, J = 11.7 Hz, 2 H), (ES⁺), atazaspiro[3.4]octane-6- 3.85-3.96 (m, 1 H), 4.13 (q, J = 7.1 Hz, 2 H).3.63 min, carboxylate 202 nm 2-6 Isomer 2: ethyl 2-[(1R,5S,6r)-6- C K(400 MHz, DMSO-d₆) δ: 0.31 (t, J = 7.1 Hz, 3 H), 0.41-0.57 (m, 8 H), 4m/z 364 (diethylcarbamoyl)-3- Example 2-1 1.11-1.26 (m, 2 H), 1.35-1.78(m, 7 H), 2.55-2.68 (m, 6H), 2.70- C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-6- and 4 2.85 (m, 2 H), 3.00 (d, J = 11.5 Hz,2 H), 3.04-3.18 (m, 1 H), 3.31 (q, (ES⁺), at azaspiro[3.4]octane-6- J =6.8 Hz, 2 H). 3.67 min, carboxylate 202 nm 2-7 Isomer 1: methyl2-[(1R,5S,6r)-6- C L then M (400 MHz, METHANOL-d₄) δ: 1.11 (t, J = 7.1Hz, 3 H), 1.28 (t, J = 7.1 1 m/z 350 (diethylcarbamoyl)-3- 17 and 4 Hz,6H), 1.93 (d, J = 8.8 Hz, 2 H), 2.03-2.25 (m, 6H), 2.32-2.43 (m, C (M +H)⁺ azabicyclo[3.1.0]hex-3-yl]-6- 1 H), 2.78-2.95 (m, 2 H), 3.35-3.43(m, 6H), 3.57 (q, J = 6.8 Hz, 2 H), (ES⁺), at azaspiro[3.4]octane-6-3.70 (s, 3 H). 3.67 min, carboxylate 210 nm 2-7 Isomer 2: methyl2-[(1R,5S,6r)-6- C L then M (400 MHz, METHANOL-d₄) δ: 1.11 (t, J = 6.8Hz, 3 H), 1.28 (t, J = 7.1 1 m/z 350 (diethylcarbamoyl)-3- 17 and 4 Hz,3 H), 1.91-2.04 (m, 6H), 2.05-2.14 (m, 2 H), 2.23-2.29 (m, 1 H), 2.55(d, J = 9.3 Hz, 2 H), C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-6- 3.08-3.20(m, 3 H), 3.29 (s, 2 H), 3.35-3.43 (m, 4 H), 3.56 (q, J = 7.0 Hz, 2 H),3.68 (s, 3 H). (ES⁺), at azaspiro[3.4]octane-6- 3.66 min, carboxylate210 nm 2-8 Isomer 1: ethyl 2-{(1R,5S,6r)-6- C N then O (400 MHz,METHANOL-d₄) δ: 1.07-1.14 (m, 3 H), 1.21-1.30 (m, 6H), 1.82-1.97 3 m/z364 [methyl(propan-2- Example 2-1 (m, 6H), 2.04-2.12 (m, 2 H), 2.21-2.25(m, 0.5H), E (M + H)⁺ yl)carbamoyl]-3- and 18 2.29-2.34 (m, 0.5H),2.40-2.48 (m, 2 H), 2.74-2.79 (m, 1 H), 2.99- (ES⁺), atazabicyclo[3.1.0]hex-3-yl}-6- 3.08 (m, 4 H), 3.32-3.39 (m, 4 H),3.53-3.59 (m, 0.5H), 3.65-3.71 (m, 0.5H), 3.32 min,azaspiro[3.4]octane-6- 4.05-4.15 (m, 2 H), 4.45-4.53 (m, 0.5H),4.68-4.77 (m, 0.5H). 202 nm carboxylate 2-8 Isomer 2: ethyl2-{(1R,5S,6r)-6- C N then O (400 MHz, METHANOL-d₄) δ: 1.06-1.14 (m, 3H), 1.21-1.29 (m, 6H), 3 m/z 364 [methyl(propan-2- Example 2-1 1.88-1.99(m, 6H), 2.01-2.10 (m, 2 H), 2.21-2.26 (m, 0.5H), E (M + H)⁺yl)carbamoyl]-3- and 18 2.29-2.33 (m, 0.5H), 2.40-2.47 (m, 2 H),2.75-2.79 (m, 1 H), 2.99- (ES⁺), at azabicyclo[3.1.0]hex-3-yl}-6- 3.10(m, 4 H), 3.24-3.28 (m, 2 H), 3.34-3.42 (m, 2 H), 3.53-3.59 3.20 min,azaspiro[3.4]octane-6- (m, 0.5H), 3.65-3.71 (m, 0.5H), 4.04-4.14 (m, 2H), 4.45-4.55 (m, 202 nm carboxylate 0.5H), 4.68-4.76 (m, 0.5H). 2-9Isomer 1: ethyl 2-{(1R,5S,6r)-6- C P then Q (400 MHz, METHANOL-d₄) δ:1.10-1.18 (m, 4 H), 1.25-1.39 (m, 10 H), 1.85-1.99 1 m/z 378[ethyl(propan-2- Example 2-1 (m, 6H), 2.02-2.14 (m, 2 H), 2.21-2.33 (m,1 H), C (M + H)⁺ yl)carbamoyl]-3- and 5 2.39-2.53 (m, 2 H), 3.06 (d, J =9.3 Hz, 3 H), 3.21-3.99 (m, 1 H), 3.36-3.39 (ES⁺), atazabicyclo[3.1.0]hex-3-yl}-6- (m, 2 H), 3.48 (q, J = 6.8 Hz, 1 H), 4.12(q, J = 6.8 Hz, 2 H), 4.42-4.70 (m, 1 H). 4.23 min,azaspiro[3.4]octane-6- 215 nm carboxylate 2-9 Isomer 2: ethyl2-{(1R,5S,6r)-6- C P then Q (400 MHz, METHANOL-d₄) δ: 1.08-1.17 (m, 4H), 1.20-1.35 (m, 10 H), 1 m/z 378.0 [ethyl(propan-2- Example 2-1 1.94(q, J = 7.3 Hz, 2 H), 1.98-2.09 (m, 4 H), 2.09-2.16 (m, 2 H), C (M + H)⁺yl)carbamoyl]-3- and 5 2.19 (m, 1 H), 2.61-2.75 (m, 2 H), 3.16-3.25 (m,2 H), 3.34-3.42 (ES⁺), at azabicyclo[3.1.0]hex-3-yl}-6- (m, 3 H), 3.46(q, J = 6.8 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 2 H), 4.24 min,azaspiro[3.4]octane-6- 4.42-4.66 (m, 1 H). 215 nm carboxylate 2-10Isomer 1: methyl 2-{(1R,5S,6r)-6- C R then S (400 MHz, METHANOL-d₄) δ:1.09-1.22 (m, 5 H), 1.22-1.38 (m, 8 H), 1 m/z 364 [ethyl(propan-2- 17and 5 1.93 (d, J = 6.8 Hz, 2 H), 2.22-2.41 (m, 7 H), 3.03-3.08 (m, 1 H),C (M + H)⁺ yl)carbamoyl]-3- 3.40-3.51 (m, 4 H), 3.69 (s, 3 H), 3.83 (d,J = 11.7 Hz, 2 H), 4.37-4.64 (m, 1 H). (ES⁺), atazabicyclo[3.1.0]hex-3-yl}-6- 3.97 min, azaspiro[3.4]octane-6- 210 nmcarboxylate 2-10 Isomer 2: methyl C R then S (400 MHz, METHANOL-d₄) δ:1.06-1.22 (m, 5 H), 1.22-1.43 (m, 8 H), 1 m/z 3642-{(1R,5S,6r)-6-[ethyl(propan-2- 17 and 5 1.91-2.07 (m, 2 H), 2.19-2.35(m, 3 H), 2.36 (d, J = 7.8 Hz, 4 H), C (M + H)⁺ yl)carbamoyl]-3-3.01-3.08 (m, 1 H), 3.40-3.50 (m, 3 H), 3.68 (s, 3 H), 3.84 (d, (ES⁺),at azabicyclo[3.1.0]hex-3-yl}-6- J = 11.2 Hz, 3 H), 4.33-4.66 (m, 1 H).4.00 min, azaspiro[3.4]octane-6- 210 nm carboxylate 2-11 Mixture ofisomers: ethyl C T (400 MHz, METHANOL-d₄) δ: 0.99-1.07 (m, 2 H), 1.13(t, J = 7.1 Hz, 1 m/z 376 2-{(1R,5S,6r)-6- Example 2-1 3 H), 1.21-1.34(m, 4 H), 1.84-2.01 (m, 6H), 2.03-2.16 (m, 2 H), C (M + H)⁺[cyclopropyl(ethyl)carbamoyl]- and 19 2.50 (t, J = 7.6 Hz, 2 H),2.66-2.71 (m, 1 H), 2.80-2.95 (m, 1 H), 3.04- (ES⁺), at3-azabicyclo[3.1.0]hex-3-yl}-6- 3.17 (m, 3 H), 3.25-3.31 (m, 1 H),3.36-3.47 (m, 6H), 4.06-4.18 4.22 min, azaspiro[3.4]octane-6- (m, 2 H).202 nm carboxylate 2-12 Isomer 1: ethyl 2-[(1R,5S,6r)-6- C U (400 MHz,DMSO-d6) δ: 1.17 (t, J = 6.7 Hz, 3 H), 1.66-1.84 (m, 8 H), 1 m/z 362(pyrrolidin-1-ylcarbonyl)-3- Example 2-1 1.84-2.03 (m, 5 H), 2.23-2.37(m, 2 H), 2.91 (d, J = 8.9 Hz, 2 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-6- and 20 2.98-3.06 (m, 1 H), 3.17-3.29 (m,6H), 3.53 (t, J = 6.7 Hz, 2 H), 4.00 (ES⁺), at azaspiro[3.4]octane-6-(q, J = 7.0 Hz, 2 H). 3.66 min, carboxylate 202 nm 2-12 Isomer 2: ethyl2-[(1R,5S,6r)-6- C U (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H),1.68-1.97 (m, 13 H), 1 m/z 362 (pyrrolidin-1-ylcarbonyl)-3- Example 2-12.19-2.38 (m, 2 H), 2.90 (d, J = 8.9 Hz, 2 H), 2.99-3.06 (m, 1 H), C(M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-6- and 20 3.16 (d, J = 10.4 Hz, 2H), 3.20-3.30 (m, 4 H), 3.53 (t, J = 6.7 Hz, 2 H), (ES⁺), atazaspiro[3.4]octane-6- 3.99 (q, J = 6.4 Hz, 2 H). 3.70 min, carboxylate202 nm 2-13 Isomer 1: ethyl 2-[(1R,5S,6r)-6- C V (400 MHz, DMSO-d₆) δ:1.17 (t, J = 6.8 Hz, 3 H), 1.32-1.45 (m, 2 H), 1 m/z 376(piperidin-1-ylcarbonyl)-3- Example 2-1 1.48-1.54 (m 2 H), 1.58 (d, J =4.6 Hz, 2 H), 1.70-1.87 (m, 6H), 1.87-2.01 C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-6- and 21 (m, 2 H), 2.03-2.07 (m, 1 H), 2.28(d, J = 8.6 Hz, 2 H), 2.90 (d, (ES⁺), at azaspiro[3.4]octane-6- J = 9.0Hz, 2 H), 2.94-3.09 (m, 1 H), 3.15-3.28 (m, 4 H), 3.38-3.46 4.05 min,carboxylate (m, 2 H), 3.46-3.58 (m, 2 H), 4.00 (q, J = 7.0 Hz, 2 H). 202nm 2-13 Isomer 2: ethyl 2-[(1R,5S,6r)-6- C V (400 MHz, DMSO-d₆) δ: 1.16(t, J = 7.0 Hz, 3 H), 1.34-1.46 (m, 2 H), 1 m/z 376(piperidin-1-ylcarbonyl)-3- Example 2-1 1.47-1.55 m, 2 H), 1.55-1.65 (m,2 H), 1.70-1.97 (m, 8 H), 2.05 (s, C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-6- and 21 1 H), 2.28 (d, J = 8.3 Hz, 2 H),2.90 (d, J = 8.8 Hz, 2 H), 2.97-3.07(m, 1 H), (ES⁺), atazaspiro[3.4]octane-6- 3.16 (d, J = 8.8 Hz, 2 H), 3.26 (q, J = 6.9 Hz, 2H), 3.37-3.44 4.07 min, carboxylate (m, 2 H), 3.47-3.59 (m, 2 H), 3.99(q, J = 6.8 Hz, 2 H). 202 nm 2-14 Isomer 1: ethyl 2-[(1R,5S,6r)-6- C Wand X (400 MHz, METHANOL-d₄) δ: 1.09-1.21 (m. 1 H), 1.22-1.38 (m, 8 H),1 m/z 390 {[(2R)-2-methylpiperidin-1- Example 2-1 1.38-1.52 (m, 2 H),1.52-1.81 (m, 5 H), 1.81-2.01 (m, 5 H), C (M + H)⁺ yl]carbonyl}-3- and22 2.01-2.16 (m, 2 H), 2.23-2.33 (m, 1 H), 2.45 (d, J = 6.8 Hz, 1.5H),(ES⁺), at azabicyclo[3.1.0]hex-3-yl]-6- 2.73-2.79 (m, 0.5H), 3.05 (d, J= 9.3 Hz, 2 H), 3.16-3.29 (m, 1 H), 4.35 min, azaspiro[3.4]octane-6-3.35-3.40 (m., 3 H), 4.12 (q, J = 6.8 Hz, 2 H), 4.33-4.79 (m, 1 H). 205nm carboxylate 2-14 Isomer 2: ethyl 2-[(1R,5S,6r)-6- C W and X (400 MHz,METHANOL-d₄) δ: 0.87-0.99 (m, 1 H), 1.13-1.21 1 m/z 390{[(2R)-2-methylpiperidin-1- Example 2-1 (m, 1 H), 1.22-1.40 (m, 7 H),1.56-1.81 (m, 4 H), 1.86-2.01 (m, 4 H), C (M + H)⁺ yl]carbonyl}-3- and22 2.02-2.12 (m, 2 H), 2.24-2.33 (m, 1 H), 2.39-2.51 (m, 2 H), 2.70-2.83(ES⁺), at azabicyclo[3.1.0]hex-3-yl]-6- (m, 1 H), 3.00-3.11 (m, 2 H),3.22-3.31 (m, 2 H), 3.35-3.44 (m, 2 H), 4.33 min, azaspiro[3.4]octane-6-4.05-4.18 (m, 3 H), 4.30-4.41 (m, 1 H), 4.53-4.64 (m, 1 H), 4.74-4.84(m, 1 H). 205 nm carboxylate 2-15 Mixture of isomers: ethyl 2- C Y (400MHz, METHANOL-d₄) δ: 1.07-1.21 (m, 2 H), 1.21-1.47 1 m/z 390[(1R,5S,6r)-6-{[(2S)-2- Example 2-1 (m, 7 H), 1.47-1.74 (m, 6H),1.79-2.02 (m, 6H), 2.02-2.17 (m, 2 H), C (M + H)⁺methylpiperidin-1-yl]carbonyl}- and 23 2.28 (d, J = 15.7 Hz, 1 H), 2.45(d, J = 7.8 Hz, 1.5H), 2.73-2.46 (ES⁺), at3-azabicyclo[3.1.0]hex-3-yl]-6- (m, 0.5H), 3.00-3.12 (m, 2 H), 3.28 (m,1 H), 3.35-3.46 (m, 3 H), 4.06-4.16 4.36 min, azaspiro[3.4]octane-6- (m,2 H), 4.33-4.82 (m, 1 H). 202 nm carboxylate 2-16 Isomer 1: ethyl2-[(1R,5S,6r)-6- C Z then AA (400 MHz, METHANOL-d₄) δ: 1.23-1.42 (m, 5H), 1.51-1.77 (m, 6H), 1 m/z 390 (azepan-1-ylcarbonyl)-3- Example 2-11.77-1.99 (m, 7 H), 2.02-2.15 (m, 2 H), 2.29-2.30 (m, 1 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-6- and 24 2.47 (d, J = 9.3 Hz, 2 H), 3.06 (d,J = 9.8 Hz, 3 H), 3.35-3.41 (m, 3 H), (ES⁺), at azaspiro[3.4]octane-6-3.52 (t, J = 6.1 Hz, 2 H), 3.70 (t, J = 6.1 Hz, 2 H), 4.12 (q, J = 6.8Hz, 2 H). 4.27 min, carboxylate 215 nm 2-16 Isomer 2: ethyl2-[(1R,5S,6r)-6- C Z then AA (400 MHz, METHANOL-d₄) δ: 1.26 (t, J = 7.1Hz, 3 H), 1.29-1.39 (m, 1 m/z 390 (azepan-1-ylcarbonyl)-3- Example 2-1 2H), 1.52-1.77 (m, 5 H), 1.83 (quin, J = 5.9 Hz, 2 H), 1.89-2.02 (m, C(M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-6- and 24 5 H), 2.02-2.14 (m, 2 H),2.29-2.30 (m, 1 H), 2.46 (d, J = 9.3 Hz, 2 H), 2.98-3.14 (m, 3 H),(ES⁺), at azaspiro[3.4]octane-6- 3.28 (d, J = 3.4 Hz, 2 H), 3.36-3.45(m, 2 H), 4.30 min, carboxylate 3.52 (t, J = 6.1 Hz, 2 H), 3.70 (t, J =6.1 Hz, 2 H), 4.11 (q, J = 6.8 Hz, 2 H). 215 nm 2-17 Isomer 1: ethyl2-[(1R,5S,6r)-6- C AB (400 MHz, METHANOL-d₄) δ: 1.26 (t, J = 7.3 Hz, 3H), 1.83-1.90 (m, 3 m/z 392 (1,4-oxazepan-4- Example 2-1 1 H), 1.90-2.04(m, 7 H), 2.04-2.12 (m, 2 H), 2.25-2.51 (m, 1 H), E (M + H)⁺ylcarbonyl)-3- and 25 2.41-2.52 (m, 2 H), 3.01-3.15 (m, 3 H), 3.28 (m, 2H), 3.36-3.43 (ES⁺), at azabicyclo[3.1.0]hex-3-yl]-6- (m, 2 H), 3.66 (t,J = 6.1 Hz, 2 H), 3.69-3.81 (m, 3 H), 3.81-3.91 (m, 3.10 min,azaspiro[3.4]octane-6- 3 H), 4.11 (q, J = 6.9 Hz, 2 H). 202 nmcarboxylate 2-17 Isomer 2: ethyl 2-[(1R,5S,6r)-6- C AB (400 MHz,METHANOL-d₄) δ: 1.23-1.32 (m, 3 H), 1.82-2.04 (m, 8 H), 3 m/z 392(1,4-oxazepan-4- Example 2-1 2.10 (t, J = 9.2 Hz, 2 H), 2.26 - (m, 1 H),2.47 (d, J = 9.2 Hz, 2 H), E (M + H)⁺ ylcarbonyl)-3- and 25 3.06 (dd, J= 9.8, 3.7 Hz, 3 H), 3.35-3.42 (m, 4 H), 3.66 (t, J = 6.1 Hz, 2 H),(ES⁺), at azabicyclo[3.1.0]hex-3-yl]-6- 3.69-3.81 (m, 3 H), 3.81-3.89(m, 3 H), 4.12 (q, J = 3.7 Hz, 2 H). 3.14 min, azaspiro[3.4]octane-6-202 nm carboxylate 2-18 Mixture of isomers: ethyl C AC (400 MHz,METHANOL-d₄) δ: 1.26 (t, J = 6.3 Hz, 3 H), 1.79- 1 m/z 3882-[(1R,5S,6r)-6-(2- Example 2-1 1.99 (m, 9 H), 1.99-2.13 (m, 2 H),2.13-2.32 (m, 4 H), 2.41 (d, J = 9.0 Hz, 2 H), C (M + H)⁺azaspiro[3.3]hept-2- and 26 2.96-3.07 (m, 3 H), 3.26 (d, J = 2.8 Hz, 1H), 3.33-3.43 (m, 3 H), (ES⁺), at ylcarbonyl)-3- 3.91 (s, 2 H), 4.10(qd, J = 7.1, 2.8 Hz, 2 H), 4.25 (s, 2 H). 4.20 min,azabicyclo[3.1.0]hex-3-yl]-6- 210 nm azaspiro[3.4]octane-6- carboxylate2-19 Isomer 2: ethyl 2-[(1R,5S,6r)-6- E AD then AE 400 MHz, METHANOL-d₄)δ: 0.53-0.61 (m, 2 H), 1.21-1.29 (m, 3 H), 2 m/z 374(4-azaspiro[2.3]hex-4- Example 2-1 1.50-1.58 (m, 2 H), 1.80-1.88 (m, 2H), 1.88-2.00 (m, 4 H), D (M + H)⁺ ylcarbonyl)-3- and 27 2.01-2.10 (m, 2H), 2.37-2.45 (m, 2 H), 2.44-2.53 (m, 2 H), 2.96- (ES⁺), atazabicyclo[3.1.0]hex-3-yl]-6- 3.09 (m, 2 H), 3.23-3.28 (m, 2 H),3.34-3.44 (m, 4 H), 3.89-3.96 1.67 min, azaspiro[3.4]octane-6- (m,0.5H), 4.04-4.15 (m, 2 H), 4.27-4.35 (m, 1.5H). 220 nm carboxylate 2-20Mixture of isomers: ethyl C AF (400 MHz, METHANOL-d₄) δ: 1.19-1.30 (m, 3H), 1.62-2.10 (m, 12 H), 1 m/z 388 2-[(1R,5S,6r)-6-(1- Example 2-12.17-2.33 (m, 1 H), 2.33-2.52 (m, 4 H), 2.81 (q, J = 10.3 Hz, 1 H),2.87-2.98 C (M + H)⁺ azaspiro[3.3]hept-1- and 28 (m, 1 H), 2.98-3.16 (m,3 H), 3.23-3.27 (m, 1 H), (ES⁺), at ylcarbonyl)-3- 3.33-3.42 (m, 3 H),3.77 (t, J = 7.7 Hz, 1 H), 4.03-4.18 (m, 3 H). 4.28 min,azabicyclo[3.1.0]hex-3-yl]-6- 202 nm azaspiro[3.4]octane-6- carboxylate2-21 Isomer 1: methyl C AG (400 MHz, METHANOL-d₄) δ: 1.24-1.37 (m, 5 H),1.56-1.78 (m, 1 H), 1 m/z 374 2-[(1R,5S,6r)-6-(1- 17 and 28 1.80-1.94(m, 4 H), 1.94-2.19 (m, 4 H), 2.19-2.37 (m, 1 H), C (M + H)⁺azaspiro[3.3]hept-1- 2.37-2.54 (m, 3 H), 2.76-2.99 (m, 2 H), 3.00-3.17(m, 2 H), 3.36- (ES⁺), at ylcarbonyl)-3- 3.41 (m, 4 H), 3.69 (s, 3 H),3.74-3.84 (m, 1 H), 4.14 (t, J = 7.6 Hz, 1 H). 3.95 min,azabicyclo[3.1.0]hex-3-yl]-6- 202 nm azaspiro[3.4]octane-6- carboxylate2-21 Isomer 2: methyl C AG (400 MHz, METHANOL-d₄) δ: 1.23-1.37 (m, 4 H),1.58-1.77 (m, 1 H), 1 m/z 374 2-[(1R,5S,6r)-6-(1- 17 and 28 1.77-2.14(m, 9 H), 2.24-2.36 (m, 1 H), 2.36-2.54 (m, 3 H), C (M + H)⁺azaspiro[3.3]hept-1- 2.76-2.88 (m, 1 H), 2.88-2.99 (m, 1 H), 2.99-3.18(m, 2 H), 3.27 (ES⁺), at ylcarbonyl)-3- (s, 1 H), 3.35-3.44 (m, 3 H),3.68 (s, 3 H), 3.75-3.86 (m, 1 H), 4.14 3.95 min,azabicyclo[3.1.0]hex-3-yl]-6- (t, J = 7.6 Hz, 1 H). 202 nmazaspiro[3.4]octane-6- carboxylate 2-22 Isomer 2: ethyl 2-[(1R,5S,6r)-6-C AH (400 MHz, METHANOL-d₄) δ: 1.24 (t, J = 7.1 Hz, 3 H), 1.82-1.99 (m,1 m/z 390 (6-oxa-1-azaspiro[3.3]hept- Example 2-1 6H), 1.99-2.11 (m, 2H), 2.36-2.52 (m, 2 H), 2.52-2.62 (m, 2 H), C (M + H)⁺ 1-ylcarbonyl)-3-and 29 2.92-3.11 (m, 3 H), 3.23-3.27(m, 2 H), 3.37 (q, J = 6.2 Hz, 2 H),3.73 (ES⁺), at azabicyclo[3.1.0]hex-3-yl]-6- (t, J = 7.6 Hz, 1 H), 4.10(quin, J = 6.8 Hz, 4 H), 4.62 (d, J = 6.8 Hz, 2 H), 3.38 min,azaspiro[3.4]octane-6- 5.14 (d, J = 7.8 Hz, 1 H), 5.32 (d, J = 7.3 Hz, 1H). 210 nm carboxylate 2-23 Isomer 2: ethyl 2-{(1R,5S,6r)-6- C AI (400MHz, METHANOL-d₄) δ: 1.26 (t, J = 7.1 Hz, 3 H), 1.88-2.01 (m, 1 m/z 352[methoxy(methyl)carbamoyl]- Example 2-1 6H), 2.01-2.11 (m, 2 H), 2.46(d, J = 9.3 Hz, 2 H), 2.56-2.68 (m, 1 H), C (M + H)⁺3-azabicyclo[3.1.0]hex-3-yl}-6- and 7 3.02-3.10 (m, 3 H), 3.16-3.24 (m,2 H), 3.25-3.29 (m, 3 H), (ES⁺), at azaspiro[3.4]octane-6- 3.36-3.44 (m,2 H), 3.80 (s, 3 H), 4.11 (q, J = 6.8 Hz, 2 H). 3.77 min, carboxylate202 nm 2-24 Isomer 1: ethyl 2-{(1R,5S,6r)-6- C AJ (400 MHz, METHANOL-d₄)δ: 1.18 (t, J = 6.8 Hz, 3 H), 1.27 (td, J = 7.0, 1 m/z 366[ethyl(methoxy)carbamoyl]- Example 2-1 3.2 Hz, 3 H), 1.82-2.01 (m, 6H),2.04-2.15 (m, 2 H), 2.47 (d, J = 9.3 C (M + H)⁺3-azabicyclo[3.1.0]hex-3-yl}-6- and 30 Hz, 2 H), 2.54-2.56 (m, 1 H),3.07 (d, J = 9.8 Hz, 3 H), 3.38 (d, J = 5.9 (ES⁺), atazaspiro[3.4]octane-6- Hz, 4 H), 3.62-3.74 (m, 2 H), 3.79 (s, 3 H), 4.12(q, J = 6.8 Hz, 2 H). 4.06 min, carboxylate 202 nm 2-24 Isomer 2: ethyl2-{(1R,5S,6r)-6- C AJ (400 MHz, METHANOL-d₄) δ: 1.18 (t, J = 6.6 Hz, 3H), 1.26 (t, J = 7.1 1 m/z 366 [ethyl(methoxy)carbamoyl]- Example 2-1Hz, 3 H), 1.88-2.01 (m, 6H), 2.02-2.13 (m, 2 H), 2.47 (d, J = 9.3 Hz, C(M + H)⁺ 3-azabicyclo[3.1.0]hex-3-yl}-6- and 30 2 H), 2.53-2.67 (m, 1H), 3.03-3.10 (m, 3 H), 3.25-3.29 (m, 2 H), (ES⁺), atazaspiro[3.4]octane-6- 3.39 (q, J = 6.7 Hz, 2 H), 3.61-3.73 (m, 2 H),3.79 (s, 3 H), 4.11 (q, 4.12 min, carboxylate J = 6.8 Hz, 2 H). 202 nm2-25 Isomer 2: ethyl 2-[(1R,5S,6r)-6- F AK (400 MHz, METHANOL-d₄) δ:1.06 (t, J = 7.5 Hz, 3 H), 1.27 (t, J = 7.0 1 m/z 350(N-methoxypropanimidoyl)- 32, 11 Hz, 3 H), 1.81-2.02 (m, 7 H), 2.02-2.15(m, 2 H), 2.46 (d, J = 9.0 Hz, C (M + H)⁺ 3-azabicyclo[3.1.0]hexan-3-and 33 2 H), 2.55 (t, J = 3.4 Hz, 1 H), 3.06 (d, J = 9.3 Hz, 3 H), 3.28(d, J = 3.7 (ES⁺), at yl]-6-azaspiro[3.4]octane-6- Hz, 2 H), 3.35-3.47(m, 3 H), 3.81 (s, 3 H), 4.11 (q, J = 7.0 Hz, 2 H). 5.09 min,carboxylate 202 nm 2-25 Isomer 4: ethyl 2-[(1R,5S,6r)-6- F AK (400 MHz,METHANOL-d₄) δ: 1.08 (t, J = 7.6 Hz, 3 H), 1.27 (t, J = 7.1 1 m/z 350(N-methoxypropanimidoyl)- 32, 11 Hz, 3 H), 1.77-1.84 (m., 3 H),1.89-2.03 (m, 4 H), 2.03-2.14 (m, 2 H), C (M + H)⁺3-azabicyclo[3.1.0]hexan-3- and 33 2.28 (q, J = 7.6 Hz, 2 H), 2.46 (d, J= 9.3 Hz, 2 H), 3.01-3.14 (m, 3 H), 3.28 (ES⁺), atyl]-6-azaspiro[3.4]octane-6- (d, J = 2.9 Hz, 2 H), 3.39 (q, J = 6.6 Hz,2 H), 3.74 (s, 3 H), 4.11 5.24 min, carboxylate (q, J = 7.1 Hz, 2 H).202 nm 2-26 Mixture of isomers: ethyl 2-[6- A AL (400 MHz, METHANOL-d₄)δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.70-1.88 (m, 1 m/z 333(trifluoromethyl)-3- 34 and 11 6H), 1.88-2.03 (m, 3 H), 2.16-2.30 (m, 2H), 2.85-3.05 (m, 3 H), C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-6-3.09-3.30 (m, 4 H), 3.91-4.10 (m, 2 H). (ES⁺), at azaspiro[3.4]octane-6-5.28 min, carboxylate 202 nm 2-27 Mixture of isomers: ethyl G AM (400MHz, DMSO-d₆) δ: 1.01 (t, J = 7.0 Hz, 3 H), 1.16 (t, J = 7.0 Hz, 3 H), 1m/z 390 2-{(1R,5S,6s)-6-[ethyl(2,2,2- 35, 36, 1.46 (s, 2 H), 1.65-1.85(m, 4 H), 1.85-1.99 (m, 2 H), 2.09-2.30 C (M + H)⁺trifluoroethyl)amino]-3- 37 and 11 (m, 3 H), 2.71 (q, J = 7.2 Hz, 2 H),2.79-2.97 (m, 3 H), 3.14 (d, J = 8.9 (ES⁺), atazabicyclo[3.1.0]hexan-3-yl}- Hz, 1 H), 3.17-3.32 (m, 5 H), 3.92-4.07(m, 2 H). 5.58 min, 6-azaspiro[3.4]octane-6- 202 nm carboxylate 2-28Isomer 1: ethyl 2-[(1R,5S,6s)-6- H AN (400 MHz, METHANOL-d₄) δ: 1.25 (t,J = 6.8 Hz, 3 H), 1.39 (d, J = 5.9 1 m/z 385 (1-phenylethoxy)-3- 38, 39Hz, 3 H), 1.50-1.61 (m, 1 H), 1.61-1.70 (m, 1 H), 1.70-2.17 (m, 7 H), C(M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-6- and 11 2.25-2.35 (m, 1 H),2.35-2.48 (m, 1 H), 2.65-2.95 (m, 3 H), (ES⁺), at azaspiro[3.4]octane-6-3.20-3.30 (m, 3 H), 3.35-3.51 (m, 1 H), 4.10 (q, J = 6.7 Hz, 2 H), 5.67min, carboxylate 4.53 (q, J = 6.4 Hz, 1 H), 7.11-7.33 (m, 1 H),7.33-7.49 (m, 4 H). 215 nm 2-28 Isomer 2: ethyl 2-[(1R,5S,6s)-6- H AN(400 MHz, METHANOL-d₄) δ: 1.25 (t, J = 7.1 Hz, 3 H), 1.39 (d, J = 6.4 1m/z 385 (1-phenylethoxy)-3- 38, 39 Hz, 3 H), 1.50-1.62 (m, 1 H),1.62-1.71 (m, 1 H), 1.74-1.92 (m, 4 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-6- and 11 1.92-2.02 (m, 2 H), 2.26-2.48 (m, 2H), 2.71-2.96 (m, 3 H), (ES⁺), at azaspiro[3.4]octane-6- 3.20 (s, 2 H),3.23-3.27 (m, 1 H), 3.35-3.43 (m, 2 H), 4.09 (q, J = 6.8 5.69 min,carboxylate Hz, 2 H), 4.53 (q, J = 6.5 Hz, 1 H), 7.20-7.42 (m, 5 H). 215nm 2-29 Isomer 2: ethyl 2-[(1R,5S,6r)-6- I AO (400 MHz, METHANOL-d₄) δ:1.21-1.28 (m, 3 H), 1.70-1.77 (m, 2 H), 1 m/z 345(1-methyl-1H-pyrazol-5-yl)- 40, 41, 1.86-2.01 (m, 4 H), 2.01-2.09 (m, 2H), 2.19-2.26 (m, 1 H), C (M + H)⁺ 3-azabicyclo[3.1.0]hex-3-yl]-6- 42and 11 2.40-2.50 (m, 2 H), 3.01-3.11 (m, 3 H), 3.25-3.28 (m, 2 H), 3.34-(ES⁺), at azaspiro[3.4]octane-6- 3.41 (m, 2 H), 3.78 (s, 3 H), 4.06-4.13(m, 2 H), 5.91-5.97 (m, 1 H), 4.10 min, carboxylate 7.34-7.43 (m, 1 H).226 nm 2-30 Isomer 1: ethyl 2-[(1R,5S,6r)-6- D AP (400 MHz, METHANOL-d₄)δ: 1.25-1.32 (m, 3 H), 1.82-2.02 (m, 6H), 1 m/z 362(2-methyl-1,3-thiazol-4-yl)-3- 6, 7, 8, 9, 2.03-2.15 (m, 2 H), 2.29-2.43(m, 1 H), 2.47 (d, J = 8.8 Hz, 2 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-6- 10 and 11 2.65 (s, 3 H), 2.98-3.19 (m, 3H), 3.35-3.41 (m, 4 H), 4.13 (q, J = 7.1 (ES⁺), atazaspiro[3.4]octane-6- Hz, 2 H), 6.89 (s, 1 H). 4.60 min, carboxylate254 nm 2-30 Isomer 2: ethyl 2-[(1R,5S,6r)-6- D AP (400 MHz, METHANOL-d₄)δ: 1.24-1.31 (m, 3 H), 1.84-1.91 (m, 2 H), 1 m/z 362(2-methyl-1,3-thiazol-4-yl)-3- 6, 7, 8, 9, 1.90-2.03 (m, 4 H), 2.03-2.14(m, 2 H), 2.32-2.42 (m, 1 H), C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-6-10 and 11 2.48 (d, J = 8.8 Hz, 2 H), 2.65 (s, 3 H), 3.02-3.19 (m, 3 H),3.25-3.29 (ES⁺), at azaspiro[3.4]octane-6- (m, 2 H), 3.36-3.44 (m, 2 H),4.12 (q, J = 7.1 Hz, 2 H), 6.89 (s, 1 H). 4.61 min, carboxylate 254 nm3-1 Mixture of isomers: ethyl 6-[(1R,5S,6r)-6- A AQ (400 MHz, DMSO-d₆)δ: 1.09-1.23 (m, 6H), 1.32-1.54 (m, 1 H), 1 m/z 337 (ethoxycarbonyl)-3-1 and 43 1.60-1.80 (m, 4 H), 1.80-2.03 (m, 5 H), 2.26 (t, J = 8.7 Hz, 2H), 2.53-2.68 C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-2- (m, 3 H), 3.00(t, J = 8.4 Hz, 2 H), 3.34 (s, 1 H), 4.00 (dq, (ES⁺), atazaspiro[3.4]octane-2- J = 18.5, 7.1 Hz, 4 H). 4.62 min, carboxylate 202nm 3-2 Mixture of isomers: ethyl 6-[(1R,5S,6r)-6- C AR (400 MHz,METHANOL-d₄) δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.18-1.35 (m, 4 m/z 364(diethylcarbamoyl)-3- Example 3-1 6H), 1.47-1.65 (m, 1 H), 1.75 (dd, J =12.8, 8.4 Hz, 1 H), 1.81-2.03 C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-2-and 4 (m, 5 H), 2.08 (dd, J = 12.7, 6.6 Hz, 1 H), 2.23 (t, J = 2.7 Hz, 1H), 2.44- (ES⁺), at azaspiro[3.4]octane-2- 2.56 (m, 2 H), 2.68 (quin, J= 7.3 Hz, 1 H), 3.15 (dd, J = 9.5, 1.7 Hz, 2 H), 3.66 min, carboxylate3.38 (q, J = 7.1 Hz, 2 H), 3.55 (q, J = 7.1 Hz, 2 H), 3.71-3.99 (m, 4H), 4.09 (q, J = 7.1 Hz, 2 H). 210 nm 3-3 Isomer 1: methyl6-[(1R,5S,6r)-6- J AS (400 MHz, METHANOL-d₄) δ: 1.11 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 1 m/z 350 (diethylcarbamoyl)-3- 6, 4 Hz, 3 H),1.47-1.63 (m, 1 H), 1.67-2.02 (m, 5 H), 2.02-2.13 (m, 1 H), 2.08 C (M +H)⁺ azabicyclo[3.1.0]hex-3-yl]-2- and 46 (dd, J = 13.0, 6.6 Hz, 1 H),2.19-2.27 (m, 1 H), 2.42-2.55 (ES⁺), at azaspiro[3.4]octane-2- (m, 2 H),2.58-2.75 (m, 1 H), 3.14 (d, J = 9.8 Hz, 2 H), 3.36-3.42 (m, 3.68 min,carboxylate 2 H), 3.48-3.60 (m, 2 H), 3.65 (s, 3 H), 3.75-3.99 (m, 4 H).210 nm 3-3 Isomer 2: methyl 6-[(1R,5S,6r)-6- J AS (400 MHz, METHANOL-d₄)δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.1 1 m/z 350(diethylcarbamoyl)-3- 6, 4 Hz, 3 H), 1.45-1.63 (m, 1 H), 1.74 (dd, J =13.0, 8.6 Hz, 1 H), 1.82- C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-2- and46 2.02 (m, 5 H), 2.07 (dd, J = 13.0, 6.6 Hz, 1 H), 2.23 (t, J = 2.7 Hz,1 H), (ES⁺), at azaspiro[3.4]octane-2- 2.40-2.56 (m, 2 H), 2.68 (quin, J= 7.3 Hz, 1 H), 3.14 (d, J = 9.3 Hz, 2 H), 3.70 min, carboxylate 3.38(q, J = 6.8 Hz, 2 H), 3.55 (q, J = 6.8 Hz, 2 H), 3.65 (s, 3 H),3.74-3.97 (m, 4 H). 210 nm 3-4 Mixture of isomers: ethyl 6- C AT (400MHz, DMSO-d₆) δ: 1.05-1.16 (m, 5 H), 1.17-1.32 (m, 8 H), 1 m/z 378{(1R,5S,6r)-6-[ethyl(propan-2- Example 3-1 1.46-1.61 (m, 1 H), 1.73 (dt,J = 12.7, 8.3 Hz, 1 H), 1.79-1.90 (m, 2 H), C (M + H)⁺ yl)carbamoyl]-3-and 5 1.90-1.99 (m, 3 H), 2.00-2.10 (m, 1 H), 2.14-2.29 (m, 1 H), (ES⁺),at azabicyclo[3.1.0]hex-3-yl}-2- 2.39-2.53 (m, 2 H), 2.55-2.73 (m, 1 H),3.12 (d, J = 9.5 Hz, 2 H), 4.28 min, azaspiro[3.4]octane-2- 3.45 (q, J =7.0 Hz, 1 H), 3.74-3.92 (m, 4 H), 4.07 (q, J = 7.2 Hz, 2 H), 202 nmcarboxylate 4.37-4.69 (m, 1 H). 4-1 Ethyl 4-[(1R,5S,6r)-6- C AU then AV(400 MHz, DMSO-d₆) δ: 1.05-1.13 (m, 3 H), 1.25 (s, 6H), 1.29-1.42 3 m/z338 (diethylcarbamoyl)-3- 73 and 4 (m, 2 H), 1.82-1.91 (m, 2 H),1.91-1.97 (m, 2 H), 2.17-2.21 (m, 1 H), E (M + H)⁺azabicyclo[3.1.0]hexan-3- 2.25-2.35 (m, 1 H), 2.50-2.57 (m, 2 H),2.79-2.96 (m, 2 H), (ES⁺), at yl]piperidine-1-carboxylate 3.14-3.21 (m,2 H), 3.32-3.41 (m, 2 H), 3.47-3.57 (m, 2 H), 3.99- 3.24 min, 4.07 (m, 2H), 4.07-4.14 (m, 2 H). 202 nm 5-1 Isomer 1: ethyl 6-[(1R,5S,6r)-6- A AWthen AX (400 MHz, DMSO-d₆) δ: 1.19-1.26 (m, 3 H), 1.26-1.33 (m, 3 H), 3m/z 323 (ethoxycarbonyl)-3- 1 and 75 1.35-1.40 (m, 1 H), 1.43-1.49 (m, 2H), 1.82-1.91 (m, 2 H), 1.91- E (M + H)⁺ azabicyclo[3.1.0]hexan-3-yl]-1.98 (m, 2 H), 2.26-2.33 (m, 2 H), 2.34-2.45 (m, 2 H), 2.57-2.63 (ES⁺),at 3-azabicyclo[3.1.1]heptane-3- (m, 1 H), 3.00-3.07 (m, 2 H), 3.38-3.55(m, 3 H), 4.04-4.23 (m, 3 H). 4.65 min, carboxylate 220 nm 5-1 Isomer 2:ethyl 6-[(1R,5S,6r)-6- A AW then AX (400 MHz, DMSO-d₆) δ: 1.21-1.31 (m,5 H), 1.33-1.40 (m, 2 H), 1.96- 3 m/z 323 (ethoxycarbonyl)-3- 1 and 752.05 (m, 3 H), 2.23-2.33 (m, 4 H), 2.36-2.40 (m, 1 H), 2.46-2.54 E (M +H)⁺ azabicyclo[3.1.0]hexan-3-yl]- (m, 1 H), 3.19-3.25 (m, 2 H),3.42-3.54 (m, 2 H), 3.65 (s, 3 H), 4.06- (ES⁺), at3-azabicyclo[3.1.1]heptane-3- 4.18 (m, 3 H). 4.69 min, carboxylate 220nm 5-2 Isomer 1: ethyl 6-[(1R,5S,6r)-6- C CY (400 MHz, METHANOL-d₄) δ:1.03-1.16 (m, 3 H), 1.22-1.34 3 m/z 350 (diethylcarbamoyl)-3- Example5-1 (m, 6H), 1.34-1.44 (m, 1 H), 1.90-2.02 (m, 2 H), 2.21-2.44 (m, 6H),E (M + H)⁺ azabicyclo[3.1.0]hexan-3-yl]- and 4 2.48-2.59 (m, 1 H),3.20-3.27 (m, 2 H), 3.35-3.42 (m, 2 H), 3.43- (ES⁺), at3-azabicyclo[3.1.1]heptane-3- 3.61 (m, 4 H), 3.62-3.75 (m, 2 H),4.08-4.23 (m, 2 H). 3.86 min, carboxylate 202 nm 6-1 Isomer 2: ethyl8-[(1R,5S,6r)-6- C AY then AZ (400 MHz, METHANOL-d₄) δ: 1.04-1.14 (m, 3H), 1.24 (s, 6H), 3 m/z 364 (diethylcarbamoyl)-3- 78 and 4 1.28-1.33 (m,1 H), 1.34-1.43 (m, 2 H), 1.73-1.81 (m, 2 H), 1.87- E (M + H)⁺azabicyclo[3.1.0]hexan-3-yl]- 1.95 (m, 2 H), 1.99-2.06 (m, 1 H),2.13-2.24 (m, 2 H), 2.34-2.41 (ES⁺), at 3-azabicyclo[3.2.1]octane-3- (m,2 H), 2.82-2.98 (m, 2 H), 3.07-3.16 (m, 2 H), 3.33-3.40 (m, 2 H),3.45-3.55 4.19 min, carboxylate (m, 2 H), 3.78-3.88 (m, 2 H), 4.06-4.15(m, 2 H). 202 nm 7-1 Isomer 2: ethyl 3-[(1R,5S,6r)-6- A BA (400 MHz,DMSO-d₆) δ: 1.13-1.21 (m, 6H), 1.59-1.89 (m, 9 H), 1 m/z 337(ethoxycarbonyl)-3- 1 and 47 1.89-1.99 (m, 2 H), 2.14-2.21 (m, 2 H),2.35-2.46 (m, 1 H), 3.15- C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-8- 3.29(m, 2 H), 3.95-4.07 (m, 6H). (ES⁺), at azabicyclo[3.2.1]octane-8- 5.28min, carboxylate 202 nm 7-2 Isomer 1: ethyl 3-{(1R,5S,6r)-6- E BB (400MHz, DMSO-d₆) δ: 0.94 (t, J = 7.0 Hz, 1 H), 1.09 (t, J = 7.2 Hz, 2 H), 5m/z 350 [ethyl(methyl)carbamoyl]-3- Example 7-1 1.15 (t, J = 7.0 Hz, 3H), 1.19-1.44 (m, 2 H), 1.57-1.74 (m, 6H), G (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-8- and 15 1.74-1.88 (m, 2 H), 1.91 (t, J =2.9 Hz, 1 H), 2.23-2.33 (m, 2 H), 2.50- (ES⁺), atazabicyclo[3.2.1]octane-8- 2.59 (m, 1 H), 2.75 (s, 2 H), 2.92 (dd, J =9.0, 4.7 Hz, 2 H), 3.00 (s, 1 H), 3.41 min, carboxylate 3.24 (q, J = 7.0Hz, 1 H), 3.39 (q, J = 7.0 Hz, 1 H), 3.96-4.05 (m, 2 H), 4.05-4.13 (m, 2H). 230-400 nm 7-2 Isomer 2: ethyl 3-{(1R,5S,6r)-6- E BB (400 MHz,DMSO-d₆) δ: 0.95 (t, J = 7.0 Hz, 2 H), 1.03-1.20 (m, 4 H), 5 m/z 350[ethyl(methyl)carbamoyl]-3- Example 7-1 1.56-1.86 (m, 10 H), 2.13 (d, J= 8.2 Hz, 2 H), 2.36-2.45 (m, 1 H), G (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-8- and 15 2.77 (s, 2 H), 2.83-2.94 (m, 1 H),3.01 (s, 1 H), 3.22 (d, J = 9.0 Hz, 2 H), (ES⁺), atazabicyclo[3.2.1]octane-8- 3.26 (d, J = 7.4 Hz, 1 H), 3.38-3.47 (m, 1H), 3.90-4.14 (m, 4 H). 4.10 min, carboxylate 230-400 nm 7-3 Isomer 1:ethyl 3-[(1R,5S,6r)-6- C BC (400 MHz, METHANOL-d₄) δ: 1.10 (t, J = 7.1Hz, 3 H), 1.19-1.36 (m, 1 m/z 364 (diethylcarbamoyl)-3- Example 7-1 6H),1.55 (q, J = 12.6 Hz, 2 H), 1.67-1.81 (m, 2 H), 1.81-1.90 (m, 2 H), C(M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-8- and 4 1.90-2.09 (m, 4 H), 2.21(t, J = 2.7 Hz, 1 H), 2.51 (d, J = 9.3 Hz, 2 H), (ES⁺), atazabicyclo[3.2.1]octane-8- 2.66 (tt, J = 11.1, 5.4 Hz, 1 H), 3.12 (d, J= 8.6 Hz, 2 H), 3.35-3.44 3.94 min, carboxylate (m, 2 H), 3.53 (q, J =7.1 Hz, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 4.22-4.32 202 nm (m, 2 H). 7-3Isomer 2: ethyl 3-[(1R,5S,6r)-6- C BC (400 MHz, METHANOL-d₄) δ: 1.12 (t,J = 7.1 Hz, 3 H), 1.27 (t, J = 7.2 1 m/z 364 (diethylcarbamoyl)-3-Example 7-1 Hz, 6H), 1.82-2.11 (m, 11 H), 2.28 (d, J = 8.8 Hz, 2 H),2.49-2.59 C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-8- and 4 (m, 1 H),3.35-3.47 (m, 4 H), 3.53 (q, J = 7.1 Hz, 2 H), 4.05-4.35 (m, 4 H).(ES⁺), at azabicyclo[3.2.1]octane-8- 4.66 min, carboxylate 202 nm 7-4Isomer 1: ethyl 3-{(1R,5S,6r)-6- C BD (400 MHz, METHANOL-d₄) δ:1.05-1.18 (m, 3 H), 1.23-1.34 (m, 9 H), 1 m/z 378 [ethyl(propan-2-Example 7-1 1.45-1.64 (m, 2 H), 1.74 (d, J = 6.3 Hz, 2 H), 1.79-1.88 (m,2 H), C (M + H)⁺ yl)carbamoyl]-3- and 5 1.88-2.07 (m, 4 H), 2.11-2.32(m, 1 H), 2.39-2.56 (m, 2 H), 2.56- (ES⁺), atazabicyclo[3.1.0]hex-3-yl}-8- 2.72 (m, 1 H), 3.10 (d, J = 9.0 Hz, 2 H),3.21-3.28 (m, 1 H), 3.44 (q, 4.30 min, azabicyclo[3.2.1]octane-8- J =7.0 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 4.20-4.30 (m, 2 H), 4.37- 210nm carboxylate 4.71 (m, 1 H). 7-4 Isomer 2: ethyl 3-{(1R,5S,6r)-6- C BD(400 MHz, METHANOL-d₄) δ: 1.10-1.18 (m, 5 H), 1.23-1.36 (m, 7 H), 1 m/z378 [ethyl(propan-2- Example 7-1 1.80-2.10 (m, 11 H), 2.28 (d, J = 8.8Hz, 2 H), 2.45-2.58 (m, C (M + H)⁺ yl)carbamoyl]-3- and 5 J = 4.8 Hz, 1H), 3.30-3.40 (m, 2 H), 3.45 (q, J = 7.0 Hz, 2 H), 4.06- (ES⁺), atazabicyclo[3.1.0]hex-3-yl}-8- 4.24 (m, 4 H), 4.28-4.78 (m, 1 H). 4.99min, azabicyclo[3.2.1]octane-8- 212 nm carboxylate 7-5 Isomer 2: ethyl3-[(1R,5S,6r)-6- J BE (400 MHz, METHANOL-d₄) δ: 1.13-1.29 (m, 6H), 1.45(d, J = 13.6 1 m/z 364 {[acetyl(ethyl)amino]methyl}- 6, 48, 49, Hz, 2H), 1.82-2.00 (m, 9 H), 2.10 (s, 1 H), 2.13 (s, 2 H), 2.19 (dd, E (M +H)⁺ 3-azabicyclo[3.1.0]hex-3-yl]-8- 50 and 47 J = 13.6, 8.7 Hz, 2 H),2.32-2.49 (m, 1 H), 3.21-3.31 (m, 4 H), 3.41- (ES⁺), atazabicyclo[3.2.1]octane-8- 3.55 (m, 2 H), 4.06-4.22 (m, 4 H). 4.17 min,carboxylate 202 nm 7-6 Isomer 2: ethyl 3-[(1R,5S,6r)-6- D BF (400 MHz,METHANOL-d₄) δ: 1.25 (t, J = 7.0 Hz, 3 H), 1.74-2.01 (m, 1 m/z 362(2-methyl-1,3-thiazol-4-yl)-3- 6, 7, 8, 9, 8 H), 2.02-2.17 (m, 2 H),2.24 (t, J = 3.0 Hz, 1 H), 2.28 (d, J = 8.5 Hz, 2 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-8- 10 and 47 2.42-2.54 (m, 1 H), 2.63 (s, 3H), 3.40 (d, J = 8.8 Hz, 2 H), 3.99- (ES⁺), atazabicyclo[3.2.1]octane-8- 4.24 (m, 4 H), 6.84 (s, 1 H). 5.56 min,carboxylate 202 nm 8-1 Mixture of isomers: ethyl 5-[(1R,5S,6r)-6- A BG(400 MHz, DMSO-d₆) δ: 1.08-1.22 (m, 6H), 1.29-1.41 (m, 1 H), 1 m/z 337(ethoxycarbonyl)-3- 1 and 53 1.41-1.52 (m, 1 H), 1.52-1.71 (m, 2 H),1.71-1.99 (m, 5 H), 2.15- C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-2- 2.35(m, 3 H), 3.02-3.26 (m, 4 H), 3.37-3.44 (m, 1 H), 3.70-3.89 (ES⁺), atazabicyclo[2.2.2]octane-2- (m, 1 H), 3.93-4.10 (m, 4 H). 5.23 min,carboxylate 202 nm 8-2 Isomer 1: ethyl (1S,4S)-5-{(1R,5S,6r)-6- E BH(400 MHz, DMSO-d₆) δ: 0.95 (t, J = 7.0 Hz, 1 H), 0.99-1.18 (m, 5 H), 5m/z 350 [ethyl(methyl)carbamoyl]-3- 56 and 15 1.36 (d, J = 12.1 Hz, 2H), 1.49-1.65 (m, 2 H), 1.70-1.91 (m, 4 H), G (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-2- 1.95-2.04 (m, 1 H), 2.14-2.24 (m, 2 H),2.24-2.35 (m, 1 H), 2.76 (ES⁺), at azabicyclo[2.2.2]octane-2- (s, 1.5H),2.82-2.89 (m, 1 H), 2.90-2.98 (m, 1 H), 3.02 (s, 1.5H), 3.79 min,carboxylate 3.09-3.29 (m, 3 H), 3.39-3.51 (m, 2 H), 3.80 (d, J = 13.7Hz, 1 H), 230-400 nm 3.98 (q, J = 7.0 Hz, 2 H). 8-2 Isomer 2: ethyl(1S,4S)-5- E BH (400 MHz, DMSO-d₆) δ: 0.94 (t, J = 7.0 Hz, 1 H),1.03-1.18 (m, 5 H), 5 m/z 350 {(1R,5S,6r)-6- 56 and 15 1.41-1.52 (m, 2H), 1.52-1.68 (m, 2 H), 1.71-1.87 (m, 4 H), 1.93- G (M + H)⁺[ethyl(methyl)carbamoyl]-3- 2.02 (m, 1 H), 2.13-2.22 (m, 2 H), 2.23-2.29(m, 1 H), 2.76 (s, 1 H), (ES⁺), at azabicyclo[3.1.0]hex-3-yl}-2-2.79-2.89 (m, 2 H), 3.02 (s, 2 H), 3.06-3.16 (m, 1 H), 3.20-3.28 3.81min, azabicyclo[2.2.2]octane-2- (m, 2 H), 3.37-3.46 (m, 2 H), 3.74-3.86(m, 1 H), 3.98 (q, J = 7.0 Hz, 2 H). 230-400 nm carboxylate 8-3 Isomer1: ethyl (1R,4R)-5- E BI (400 MHz, CHLOROFORM- d) δ: 1.04-1.14 (m, 1 H),1.17-1.32 (m, 5 m/z 350 {(1R,5S,6r)-6- 59 and 15 5 H), 1.43-1.73 (m, 4H), 1.74-1.89 (m, 2 H), 1.89-2.01 (m, 2 H), G (M + H)⁺[ethyl(methyl)carbamoyl]-3- 2.04-2.13 (m, 1 H), 2.21-2.36 (m, 2 H), 2.92(d, J = 1.56 Hz, 3 H), (ES⁺), at azabicyclo[3.1.0]hexan-3-yl}- 3.00-3.09(m, 1 H), 3.11 (s, 1 H), 3.13-3.28 (m, 2 H), 3.36-3.45 3.87 min,2-azabicyclo[2.2.2]octane-2- (m, 1 H), 3.46-3.60 (m, 2 H), 3.92-3.97 (m,1 H), 4.03-4.08 (m, 1 H), 230-400 nm carboxylate 4.09-4.19 (m, 2 H). 8-4Isomer 1: ethyl (1S,4S)-5- E BJ then BK (400 MHz, CHLOROFORM-d) δ: 1.08(t, J = 7.0 Hz, 3 H), 1.17-1.28 5 m/z 364 [(1R,5S,6r)-6- 56 and 4 (m,6H), 1.41-1.70 (m, 4 H), 1.73-1.87 (m, 2 H), 1.87-1.99 (m, 3 H), 2.03 G(M + H)⁺ (diethylcarbamoyl)-3- (d, J = 9.8 Hz, 1 H), 2.21-2.33 (m, 3 H),3.02 (dd, J = 14.8, 9.0 (ES⁺), at azabicyclo[3.1.0]hexan-3-yl]- Hz, 1H), 3.11-3.21 (m, 2 H), 3.35 (q, J = 6.8 Hz, 2 H), 3.39-3.48 (m, 4.09min, 2-azabicyclo[2.2.2]octane-2- 2 H), 3.48-3.57 (m, 1 H), 3.89-4.05(m, 1 H), 4.11 (q, J = 7.0 Hz, 2 H). 230-400 nm carboxylate 8-4 Isomer2: ethyl (1S,4S)-5- E BJ then BK (400 MHz, CHLOROFORM-d) δ: 1.08 (t, J =7.0 Hz, 3 H), 1.17-1.29 5 m/z 364 [(1R,5S,6r)-6- 56 and 4 (m, 6H),1.34-1.48 (m, 2 H), 1.55-1.67 (m, 1 H), 1.67-1.79 (m, 1 H), G (M + H)⁺(diethylcarbamoyl)-3- 1.79-1.90 (m, 2 H), 1.90-2.07 (m, 4 H), 2.22-2.37(m, 3 H), (ES⁺), at azabicyclo[3.1.0]hexan-3-yl]- 2.99 (d, J = 9.0 Hz, 1H), 3.15 (t, J = 8.2 Hz, 1 H), 3.25-3.32 (m, 1 H), 4.11 min,2-azabicyclo[2.2.2]octane-2- 3.36 (q, J = 6.8 Hz, 3 H), 3.40-3.50 (m, 2H), 3.85-4.03 (m, 1 H), 230-400 nm carboxylate 4.10 (q, J = 7.0 Hz, 2H). 8-5 Isomer 1: ethyl (1R,4R)-5- E BI (400 MHz, CHLOROFORM-d) δ:1.06-1.14 (m, 3 H), 1.19-1.31 (m, 5 m/z 364 [(1R,5S,6r)-6- 59 and 4 7H), 1.43-1.62 (m, 3 H), 1.78-1.89 (m, 2 H), 1.90-2.01 (m, 2 H), G (M +H)⁺ (diethylcarbamoyl)-3- 2.02-2.09 (m, 1 H), 2.23-2.35 (m, 3 H),3.00-3.09 (m, 1 H), 3.14- (ES⁺), at azabicyclo[3.1.0]hexan-3-yl]- 3.26(m, 2 H), 3.33-3.41 (m, 2 H), 3.41-3.50 (m, 2 H), 3.50-3.59 4.19 min,2-azabicyclo[2.2.2]octane-2- (m, 1 H), 3.92-3.96 (m, 1 H), 4.02-4.08 (m,1 H), 4.08-4.19 (m, 2 H). 230-400 nm carboxylate 8-5 Isomer 2: ethyl(1R,4R)-5- E BI (400 MHz, CHLOROFORM-d) δ: 1.11 (t, J = 7.22 Hz, 3 H),1.25 (q, 5 m/z 364 [(1R,5S,6r)-6- 59 and 4 J = 7.16 Hz, 6H), 1.36-1.47(m, 2 H), 1.69-1.80 (m, 1 H), 1.82-1.93 G (M + H)⁺ (diethylcarbamoyl)-3-(m, 2 H), 1.94-2.09 (m, 4 H), 2.27-2.32 (m, 2 H), 2.33-2.40 (m, 1 H),(ES⁺), at azabicyclo[3.1.0]hexan-3-yl]- 2.98-3.04 (m, 1 H), 3.15-3.21(m, 1 H), 3.27-3.34 (m, 1 H), 4.18 min, 2-azabicyclo[2.2.2]octane-2-3.35-3.42 (m, 3 H), 3.42-3.52 (m, 2 H), 3.89-3.94 (m, 1 H), 4.00-230-400 nm carboxylate 4.06 (m, 1 H), 4.13 (q, J = 7.16 Hz, 2 H). 8-6Isomer 1: methyl 5- C BL then BM (400 MHz, METHANOL-d₄) δ: 1.11 (t, J =7.1 Hz, 3 H), 1.22-1.37 (m, 4 m/z 350 [(1R,5S,6r)-6- 61 and 4 6H),1.48-1.78 (m, 4 H), 1.90-2.03 (m, 4 H), 2.23 (d, J = 2.4 Hz, 1 H), C(M + H)⁺ (diethylcarbamoyl)-3- 2.37-2.51 (m, 2 H), 3.11-3.25 (m, 1 H),3.25-2.30 (m, 1 H), (ES⁺), at azabicyclo[3.1.0]hex-3-yl]-2- 3.36-3.43(m, 3 H), 3.49-3.63 (m, 2 H), 3.65-3.72 (m, 3 H), 3.91- 3.72 min,azabicyclo[2.2.2]octane-2- 4.00 (m, 1 H). 210 nm carboxylate 8-6 Isomer2: methyl 5- C BL then BM (400 MHz, METHANOL-d₄) δ: 1.11 (t, J = 7.1 Hz,3 H), 1.23-1.39 (m, 4 m/z 350 [(1R,5S,6r)-6- 61 and 4 6H), 1.57-1.77 (m,4 H), 1.89-2.02 (m, 4 H), 2.19-2.55 (m, 1 H), C (M + H)⁺(diethylcarbamoyl)-3- 2.31-2.48 (m, 3 H), 3.09-3.19 (m, 1 H), 3.21-3.30(m, 1 H), 3.38 (ES⁺), at azabicyclo[3.1.0]hex-3-yl]-2- (q, J = 7.3 Hz, 2H), 3.51-3.62 (m, 2 H), 3.66-3.71 (m, 3 H), 3.92- 3.69 min,azabicyclo[2.2.2]octane-2- 4.01 (m, 1 H). 210 nm carboxylate 8-7 Mixtureof isomers: ethyl C BN (400 MHz, METHANOL-d₄) δ: 1.10-1.18 (m, 5 H),1.24-1.32 (m, 7 H), 1 m/z 378 5-{(1R,5S,6r)-6-[ethyl(propan-2- Example8-1 1.43-1.54 (m, 1 H), 1.57-1.85 (m, 3 H), 1.88-2.08 (m, 5 H), C (M +H)⁺ yl)carbamoyl]-3- and 5 2.18-2.28 (m, 1 H), 2.31-2.44 (m, 3 H),3.06-3.20 (m, 1 H), 3.22- (ES⁺), at azabicyclo[3.1.0]hex-3-yl}-2- 3.26(m, 1 H), 3.34-3.39 (m, 2 H), 3.41-3.52 (m, 2 H), 3.92-4.00 4.71 min,azabicyclo[2.2.2]octane-2- (m, 1 H), 4.08-4.18 (m, 2 H), 4.40-4.71 (m, 1H). 210 nm carboxylate 8-8 Mixture of isomers: ethyl E BO (400 MHz,CHLOROFORM-d₄) δ: 0.69-0.81 (m, 2 H), 0.81-0.94 (m, 5 m/z 376(1S,4S)-5-{(1R,5S,6r)-6- 56 and 19 2 H), 1.08 (t, J = 7.0 Hz, 3 H),1.18-1.25 (m, 3 H), 1.31-2.19 (m, 10 H), G (M + H)⁺[cyclopropyl(ethyl)carbamoyl]- 2.19-2.29 (m, 3 H), 2.48-2.56 (m, 1 H),2.67-2.78 (m, 1 H), (ES⁺), at 3-azabicyclo[3.1.0]hex-3-yl}-2- 2.93-3.06(m, 1 H), 3.10-3.21 (m, 1 H), 3.23-3.38 (m, 2 H), 3.39- 4.40 min,azabicyclo[2.2.2]octane-2- 3.54 (m, 1 H), 3.83-4.02 (m, 1 H), 4.08 (q, J= 7.0 Hz, 2 H). 230-400 nm carboxylate 8-9 Isomer 1: ethyl5-{(1R,5S,6r)-6- C BP (400 MHz, METHANOL-d₄) δ: 1.26 (q, J = 7.0 Hz, 3H), 1.40-1.59 (m, 1 m/z 352 [methoxy(methyl)carbamoyl]- Example 8-1 2H), 1.73 (t, J = 12.0 Hz, 2 H), 1.87-1.99 (m, 4 H), 1.99-2.13 (m, 1 H),C (M + H)⁺ 3-azabicyclo[3.1.0]hexan-3- and 7 2.27-2.46 (m, 3 H),2.49-2.63 (m, 1 H), 3.11 (dd, J = 9.3, 3.4 Hz, (ES⁺), atyl}-2-azabicyclo[2.2.2]octane- 1 H), 3.16-3.25 (m, 3 H), 3.28 (dd, J =9.3, 3.4 Hz, 2 H), 3.35-3.46 4.12 min, 2-carboxylate (m, 1 H), 3.78 (s,3 H), 3.91-3.70 (m, 1 H), 4.12 (q, J = 6.8 Hz, 2 H). 210 nm 8-10 Isomer1: ethyl 5-{(1R,5S,6r)-6- C BQ (400 MHz, METHANOL-d₄) δ: 1.18 (t, J =6.8 Hz, 3 H), 1.26 (q, J = 7.3 1 m/z 366 [ethyl(methoxy)carbamoyl]-Example 8-1 Hz, 3 H), 1.41-1.59 (m, 2 H), 1.63-1.85 (m, 2 H), 1.88-2.10(m, 5 H), C (M + H)⁺ 3-azabicyclo[3.1.0]hex-3-yl}-2- and 30 2.29-2.45(m, 3 H), 2.46-2.62 (m, 1 H), 3.11 (dd, J = 9.0, 3.2 Hz, (ES⁺), atazabicyclo[2.2.2]octane-2- 1 H), 3.29 (dd, J = 9.3, 2.9 Hz, 1 H),3.35-3.48 (m, 2 H), 3.62-3.73 4.44 min, carboxylate (m, 2 H), 3.78 (s, 3H), 3.87-3.99 (m, 1 H), 4.12 (q, J = 6.8 Hz, 2 H). 202 nm 8-10 Isomer 2:ethyl 5-{(1R,5S,6r)-6- C BQ (400 MHz, METHANOL-d₄) δ: 1.18 (t, J = 6.4Hz, 3 H), 1.28 (q, J = 7.3 1 m/z 366 [ethyl(methoxy)carbamoyl]- Example8-1 Hz, 3 H), 1.52-1.68 (m, 3 H), 1.72 (d, J = 3.4 Hz, 1 H), 1.75-1.84(m, C (M + H)⁺ 3-azabicyclo[3.1.0]hex-3-yl}-2- and 30 1 H), 1.89-2.00(m, 3 H), 2.29-2.43 (m, 3 H), 2.47-2.63 (m, 1 H), (ES⁺), atazabicyclo[2.2.2]octane-2- 3.14 (dd, J = 9.3, 5.4 Hz, 1 H), 3.17-3.24(m, 1 H), 3.27 (dd, J = 9.3, 4.53 min, carboxylate 3.9 Hz, 2 H),3.53-3.63 (m, 1 H), 3.67 (d, J = 7.8 Hz, 2 H), 3.77 (s, 3 H), 202 nm3.91-4.02 (m, 1 H), 4.13 (q, J = 7.2 Hz, 2 H). 9-1 Isomer 1: ethyl3-{(1R,5S,6r)-6- C BR (400 MHz, METHANOL-d₄) δ: 1.10 (t, J = 7.2 Hz, 1H), 1.19-1.38 (m, 1 m/z 364 [ethyl(methyl)carbamoyl]-3- 64 and 15 7 H),1.43-1.68 (m, 5 H), 1.91-1.97 (m., 2 H), 1.97-2.13 (m, 2 H), E (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-9- 2.27 (t, J = 7.6 Hz, 3 H), 2.52 (d, J =8.5 Hz, 2 H), 2.92 (s, 2 H), 3.13- (ES⁺), at azabicyclo[3.3.1]nonane-9-3.26 (m, 3 H), 3.41 (q, J = 7.0 Hz, 1 H), 3.58 (q, J = 7.0 Hz, 1 H),4.13 3.74 min, carboxylate (q, J = 7.0 Hz, 2 H), 4.40-4.51 (m, 2 H). 202nm 9-1 Isomer 2: ethyl 3-{(1R,5S,6r)-6- C BR (400 MHz, METHANOL-d₄) δ:1.09 (t, J = 7.2 Hz, 1 H), 1.16-1.34 (m, 1 m/z 364[ethyl(methyl)carbamoyl]-3- 64 and 15 5 H), 1.53-1.80 (m, 7 H),1.88-2.04 (m, 5 H), 2.20-2.31 (m, 1 H), E (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-9- 2.43-2.64 (m, 2 H), 2.92 (s, 2 H),2.98-3.12 (m, 1 H), 3.12-3.21 (ES⁺), at azabicyclo[3.3.1]nonane-9- (m, 3H), 3.40 (q, J = 7.2 Hz, 1 H), 3.57 (q, J = 7.0 Hz, 1 H), 4.14 (q, 3.75min, carboxylate J = 7.0 Hz, 2 H), 4.29-4.40 (m, 2 H). 202 nm 9-2 Isomer1: ethyl 3-[(1R,5S,6r)-6- C BS then BT (400 MHz, METHANOL-d₄) δ: 1.10(t, J = 7.2 Hz, 3 H), 1.19-1.37 (m, 1 m/z 378 (diethylcarbamoyl)-3- 64and 4 6H), 1.55-1.85 (m, 7 H), 1.87-2.02 (m, 4 H), 2.18-2.27 (m, 1 H), C(M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-9- 2.53 (d, J = 9.5 Hz, 2 H),2.62-2.66 (m, 1 H), 2.99-3.13 (m, 1 H), (ES⁺), atazabicyclo[3.3.1]nonane-9- 3.16 (dd, J = 9.5, 4.8 Hz, 2 H), 3.35-3.44(m, 2 H), 3.46-3.60 (m, 2 H), 4.15 min, carboxylate 4.14 (q, J = 7.0 Hz,2 H), 4.28-4.42 (m, 2 H). 202 nm 9-2 Isomer 2: ethyl 3-[(1R,5S,6r)-6- CBS then BT (400 MHz, METHANOL-d₄) δ: 1.11 (t, J = 7.2 Hz, 3 H),1.22-1.37 (m, 1 m/z 378 (diethylcarbamoyl)-3- 64 and 4 9 H), 1.45-1.66(m, 4 H), 1.92-1.96 (m, 2 H), 1.98-2.12 (m, 2 H), C (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-9- 2.23 (t, J = 2.9 Hz, 1 H), 2.24-2.36 (m, 2H), 2.53 (d, J = 9.2 Hz, 2 H), (ES⁺), at azabicyclo[3.3.1]nonane-9- 3.18(d, J = 9.5 Hz, 2 H), 3.36-3.45 (m, 2 H), 3.55 (q, J = 7.3 Hz, 2 H),4.07 min, carboxylate 4.12 (q, J = 7.0 Hz, 2 H), 4.39-4.58 (m, 2 H). 202nm 9-3 Isomer 1: methyl 3-[(1R,5S,6r)-6- C BU (400 MHz, METHANOL-d₄) δ:1.10 (t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.2 1 m/z 364(diethylcarbamoyl)-3- 66 and 4 Hz, 3 H), 1.57-1.85 (m, 6H), 1.88-2.03(m, 4 H), 2.06 (s, 2 H), 2.21 E (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-9-(t, J = 2.6 Hz, 1 H), 2.53 (d, J = 9.2 Hz, 2 H), 3.06 (tt, J = 11.4, 5.5Hz, 1 H), (ES⁺), at azabicyclo[3.3.1]nonane-9- 3.12-3.20 (m, 2 H),3.36-3.42 (m, 2 H), 3.53 (q, J = 7.0 Hz, 2 H), 3.72 min, carboxylate3.70 (s, 3 H), 4.27-4.39 (m, 2 H). 202 nm 9-3 Isomer 2: methyl3-[(1R,5S,6r)-6- C BU (400 MHz, METHANOL-d₄) δ: 1.11 (t, J = 7.0 Hz, 3H), 1.22-1.38 (m, 1 m/z 364 (diethylcarbamoyl)-3- 66 and 4 5 H),1.45-1.75 (m, 5 H), 1.90-2.01 (m, 3 H), 2.01-2.13(m, 2 H), E (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-9- 2.18-2.37 (m, 2 H), 2.53 (d, J = 9.5 Hz, 2H), 3.13-3.24 (m, 2 H), (ES⁺), at azabicyclo[3.3.1]nonane-9- 3.36-3.43(m, 3 H), 3.49-3.60 (m, 2 H), 3.64-3.76 (m, 2 H), 4.30- 3.74 min,carboxylate 4.51 (m, 2 H). 202 nm 10-1 Isomer 1: ethyl 7-{(1R,5S,6r)-6-C BV then BW (400 MHz, METHANOL-d₄) δ: 1.10 (t, J = 7.3 Hz, 1 H),1.23-1.33 (m, 1 m/z 366 [ethyl(methyl)carbamoyl]-3- 69 and 15 5 H), 1.57(t, J = 11.9 Hz, 2 H), 1.91-1.95 (m, 2 H), 2.01 (tt, J = 11.8, E (M +H)⁺ azabicyclo[3.1.0]hex-3-yl}-3- 5.6 Hz, 1 H), 2.28 (d, J = 8.5 Hz, 1H), 2.31-2.41 (m, 2 H), 2.51 (d, (ES⁺), at oxa-9- J = 9.2 Hz, 2 H), 2.92(s, 2 H), 3.14-3.20 (m, 3 H), 3.37-3.44 (m, 1 H), 3.20 min,azabicyclo[3.3.1]nonane-9- 3.48-3.66 (m, 5 H), 4.12-4.28 (m, 4 H). 202nm carboxylate 10-1 Isomer 2: ethyl 7-{(1R,5S,6r)-6- C BV then BW (400MHz, METHANOL-d₄) δ: 1.09 (t, J = 7.0 Hz, 1 H), 1.22-1.32 (m, 1 m/z 366[ethyl(methyl)carbamoyl]-3- 69 and 15 4 H), 1.62 (t, J = 11.9 Hz, 2 H),1.89-1.99 (m, 2 H), 2.06 (dd, J = 13.1, E (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-3- 5.2 Hz, 2 H), 2.21-2.28 (m, 1 H), 2.54 (d,J = 8.5 Hz, 2 H), 2.92 (s, 1 H), (ES⁺), at oxa-9- 3.13-3.19 (m, 3 H),3.35-3.44 (m, 4 H), 3.57 (q, J = 7.3 Hz, 1 H), 3.24 min,azabicyclo[3.3.1]nonane-9- 3.68 (d, J = 11.0 Hz, 2 H), 3.79-3.92 (m, 2H), 4.06-4.13 (m, 2 H), 202 nm carboxylate 4.17 (q, J = 7.1 Hz, 2 H).10-2 Isomer 1: ethyl 7-[(1R,5S,6r)-6- C BX then BY (400 MHz,METHANOL-d₄) δ: 0.80-1.01 (m, 2 H), 1.11 (t, J = 7.1 Hz, 1 m/z 380(diethylcarbamoyl)-3- 69 and 4 2 H), 1.21-1.44 (m, 9 H), 1.49-1.69 (m, 2H), 1.92-1.95 (m, 2 H), C (M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-3-1.97-2.10 (m, 1 H), 2.26 (t, J = 2.7 Hz, 1 H), 2.28-2.36 (m, 2 H), 2.52(ES⁺), at oxa-9- (d, J = 9.3 Hz, 1 H), 3.18 (d, J = 9.3 Hz, 1 H),3.35-3.42 (m, 2 H), 3.47- 3.46 min, azabicyclo[3.3.1]nonane-9- 3.68 (m,4 H), 4.08-4.33 (m, 4 H). 210 nm carboxylate 10-2 Isomer 2: ethyl7-[(1R,5S,6r)-6- C BX then BY (400 MHz, METHANOL-d₄) δ: 1.10 (t, J = 6.8Hz, 3 H), 1.20-1.38 (m, 1 m/z 380 (diethylcarbamoyl)-3- 69 and 4 6H),1.53-1.71 (m, 2 H), 1.91-1.98 (m, 2 H), 2.07 (dd, J = 13.2, 5.4 C (M +H)⁺ azabicyclo[3.1.0]hex-3-yl]-3- Hz, 2 H), 2.18-2.26 (m, 1 H), 2.55 (d,J = 9.3 Hz, 2 H), 3.17 (dd, (ES⁺), at oxa-9- J = 9.3, 5.4 Hz, 2 H),3.35-3.46 (m, 3 H), 3.54 (q, J = 7.3 Hz, 2 H), 3.68 3.49 min,azabicyclo[3.3.1]nonane-9- (d, J = 11.2 Hz, 2 H), 3.79-3.92 (m, 2 H),4.05-4.14 (m, 2 H), 4.14- 210 nm carboxylate 4.26 (m, 2 H). 10-3 Isomer1: methyl 7-[(1R,5S,6r)-6- C BZ then CA (400 MHz, METHANOL-d₄) δ: 1.09(s, 3 H), 1.20-1.28 (m, 3 H), 1.50- 1 m/z 366 (diethylcarbamoyl)-3- 71and 4 1.60 (m, 2 H), 1.88-1.94 (m, 2 H), 1.95-2.05 (m, 1 H), 2.21-2.26 E(M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-3- (m, 1 H), 2.27-2.39 (m, 2 H),2.45-2.54 (m, 2 H), 3.11-3.20 (m, 2 H), 3.33-3.40 (m, 2 H), (ES⁺), atoxa-9- 3.46-3.64 (m, 6H), 3.70 (s, 3 H), 4.16-4.23 (m, 2 H). 3.06 min,azabicyclo[3.3.1]nonane-9- 202 nm carboxylate 10-3 Isomer 2: methyl7-[(1R,5S,6r)-6- C BZ then CA (400 MHz, METHANOL-d₄) δ: 1.10 (t, J = 7.3Hz, 3 H), 1.26 (t, J = 7.0 1 m/z 366 (diethylcarbamoyl)-3- 71 and 4 Hz,3 H), 1.52-1.72 (m, 2 H), 1.90-1.95 (m, 2 H), 2.06 (dd, J = 13.1, E (M +H)⁺ azabicyclo[3.1.0]hex-3-yl]-3- 4.6 Hz, 2 H), 2.16-2.28 (m, 1 H), 2.54(d, J = 9.2 Hz, 2 H), 3.16 (dd, (ES⁺), at oxa-9- J = 9.5, 6.4 Hz, 2 H),3.35-3.46 (m, 3 H), 3.49-3.62 (m, 2 H), 3.62- 3.07 min,azabicyclo[3.3.1]nonane-9- 3.71 (m, 2 H), 3.73 (s, 3 H), 3.85 (dd, J =16.5, 11.6 Hz, 2 H), 4.03- 202 nm carboxylate 4.10 (m, 2 H). 10-4 Isomer1: ethyl 7-{(1R,5S,6r)-6- C CB then CC (400 MHz, METHANOL-d₄) δ: 1.10(d, J = 6.85 Hz, 3 H), 1.23-1.31 3 m/z 380[methyl(propan-2-yl)carbamoyl]-3- 69 and 18 (m, 6H), 1.55-1.67 (m, 2 H),1.92-2.00 (m, 2 H), 2.19-2.25 (m, 1 H), E (M + H)⁺azabicyclo[3.1.0]hexan-3-yl}- 2.28-2.39 (m, 2 H), 2.51-2.63 (m, 2 H),2.77 (s, 1.5H), 3.00 (s, (ES⁺), at 3-oxa-9- 1.5H), 3.17-3.26 (m, 2 H),3.48-3.56 (m, 2 H), 3.57-3.71 (m, 2 H), 2.95 min,azabicyclo[3.3.1]nonane-9- 4.10-4.25 (m, 4 H), 4.46-4.54 (m, 1 H),4.67-4.77 (m, 1 H). 202 nm carboxylate 10-4 Isomer 2: ethyl7-{(1R,5S,6r)-6- C CB then CC (400 MHz, METHANOL-d₄) δ: 1.09 (d, J =6.85 Hz, 3 H), 1.22-1.31 3 m/z 380 [methyl(propan-2-yl)carbamoyl]-3- 69and 18 (m, 6H), 1.55-1.68 (m, 2 H), 1.92-1.98 (m, 2 H), 2.02-2.11 (m, 2H), E (M + H)⁺ azabicyclo[3.1.0]hexan-3-yl}- 2.17-2.30 (m, 1 H),2.53-2.65 (m, 2 H), 2.76 (s, 1.5H), 2.99 (s, (ES⁺), at 3-oxa-9- 1.5H),3.14-3.23 (m, 2 H), 3.62-3.71 (m, 2 H), 3.78-3.90 (m, 2 H), 2.99 min,azabicyclo[3.3.1]nonane-9- 4.04-4.12 (m, 2 H), 4.12-4.19 (m, 2 H),4.43-4.51 (m, 1 H), 4.68- 202 nm carboxylate 4.76 (m, 1 H). 10-5 Isomer1: methyl 7-((1R,5S,6r)-6- C CD then CE (400 MHz, METHANOL-d₄) δ: 1.10(d, J = 7.02 Hz, 3 H), 1.25 (d, 3 m/z 366 (isopropyl(methyl)carbamoyl)-71 and 18 J = 6.71 Hz, 3 H), 1.50-1.61 (m, 2 H), 1.89-1.95 (m, 2 H),1.95-2.05 E (M + H)⁺ 3-azabicyclo[3.1.0]hexan-3- (m, 1 H), 2.26-2.38 (m,2 H), 2.46-2.54 (m, 2 H), 2.76 (s, 1.5H), (ES⁺), at yl)-3-oxa-9- 3.00(s, 1.5H), 3.12-3.19 (m, 2 H), 3.46-3.66 (m, 4 H), 3.70 (s, 3 H), 2.70min, azabicyclo[3.3.1]nonane-9- 4.15-4.23 (m, 2 H), 4.45-4.53 (m, 1 H),4.66-4.76 (m, 1 H). 202 nm carboxylate 10-5 Isomer 2: methyl7-((1R,5S,6r)-6- C CD then CE (400 MHz, METHANOL-d₄) δ: 1.09 (d, J =6.71 Hz, 3 H), 1.20-1.27 3 m/z 366 (isopropyl(methyl)carbamoyl)- 71 and18 (m, 3 H), 1.53-1.67 (m, 2 H), 1.90-1.96 (m, 2 H), 2.00-2.10 (m, 2 H),E (M + H)⁺ 3-azabicyclo[3.1.0]hexan-3- 2.17-2.29 (m, 1 H), 2.46-2.55 (m,2 H), 2.76 (s, 1.5H), 2.99 (s, (ES⁺), at yl)-3-oxa-9- 1.5H), 3.10-3.19(m, 2 H), 3.61-3.69 (m, 2 H), 3.71 (d, J = 0.92 Hz, 2.71 min,azabicyclo[3.3.1]nonane-9- 3 H), 3.77-3.89 (m, 2 H), 4.03-4.09 (m, 2 H),4.43-4.52 (m, 1 H), 202 nm carboxylate 4.66-4.76 (m, 1 H). 10-6 Isomer1: ethyl 7-{(1R,5S,6r)-6- C CF (400 MHz, METHANOL-d₄) δ: 0.85-0.98 (m, 1H), 1.06-1.18 (m, 4 H), 3 m/z 394 [ethyl(propan-2-yl)carbamoyl]-3- 69and 5 1.23-1.33 (m, 8 H), 1.49-1.63 (m, 2 H), 1.83-2.09 (m, 3 H), E (M +H)⁺ azabicyclo[3.1.0]hex-3-yl}-3- 2.18-2.24 (m, 1 H), 2.25-2.40 (m, 2H), 2.44-2.56 (m, 2 H), 3.10- (ES⁺), at oxa-9- 3.24 (m, 2 H), 3.25-3.29(m, 1 H), 3.40-3.65 (m, 5 H), 4.09-4.25 3.38 min,azabicyclo[3.3.1]nonane-9- (m, 3 H), 4.39-4.70 (m, 1 H). 202 nmcarboxylate 10-6 Isomer 2: ethyl 7-{(1R,5S,6r)-6- C CF (400 MHz,METHANOL-d₄) δ: 1.05-1.19 (m, 4 H), 1.19-1.33 (m, 6H), 3 m/z 394[ethyl(propan-2-yl)carbamoyl]-3- 69 and 5 1.63 (t, J = 12.2 Hz, 2 H),1.86-1.98 (m, 2 H), 2.07 (dd, J = 13.1, E (M + H)⁺azabicyclo[3.1.0]hex-3-yl}-3- 5.2 Hz, 2 H), 2.15-2.32 (m, 1 H),2.45-2.61 (m, 2 H), 3.11-3.22 (m, (ES⁺), at oxa-9- 2 H), 3.26-3.31 (m, 1H), 3.37 (s, 2 H), 3.41-3.53 (m, 2 H), 3.68 (d, 3.44 min,azabicyclo[3.3.1]nonane-9- J = 11.6 Hz, 2 H), 3.77-3.95 (m, 2 H),4.03-4.13 (m, 2 H), 4.17 (q, 202 nm carboxylate J = 7.1 Hz, 2 H),4.39-4.70 (m, 1 H). 10-7 Isomer 1: methyl 7-{(1R,5S,6r)-6- C CG then CH(400 MHz, METHANOL-d₄) δ: 1.07-1.19 (m, 6H), 1.22-1.37 (m, 3 H), 3 m/z380 [ethyl(propan-2-yl)carbamoyl]-3- 71 and 5 1.50-1.65 (m, 2 H),1.90-1.96 (m, 2 H), 1.95-2.07 (m, 1 H), E (M + H)⁺azabicyclo[3.1.0]hexan-3-yl}- 2.27-2.40 (m, 2 H), 2.45-2.57 (m, 2 H),3.11-3.21 (m, 2 H), 3.41- (ES⁺), at 3-oxa-9- 3.66 (m, 6H), 3.71 (s, 3H), 4.16-4.26 (m, 2 H), 4.42-4.51 (m, 1 H), 3.03 min,azabicyclo[3.3.1]nonane-9- 4.59-4.69 (m, 1 H). 202 nm carboxylate 10-7Isomer 2: methyl 7-{(1R,5S,6r)-6- C CG then CH (400 MHz, METHANOL-d₄) δ:1.06-1.18 (m, 6H), 1.23-1.31 (m, 3 H), 3 m/z 380[ethyl(propan-2-yl)carbamoyl]-3- 71 and 5 1.53-1.67 (m, 2 H), 1.91-1.97(m, 2 H), 2.00-2.10 (m, 2 H), E (M + H)⁺ azabicyclo[3.1.0]hexan-3-yl}-2.16-2.28 (m, 1 H), 2.47-2.58 (m, 2 H), 3.11-3.19 (m, 2 H), 3.34- (ES⁺),at 3-oxa-9- 3.50 (m, 2 H), 3.61-3.70 (m, 2 H), 3.71 (s, 3 H), 3.78-3.88(m, 2 H), 3.04 min, azabicyclo[3.3.1]nonane-9- 4.03-4.11 (m, 2 H),4.40-4.49 (m, 1 H) 4.57-4.68 (m, 1 H). 202 nm carboxylate 10-8 Isomer 1:ethyl 7-{(1R,5S,6r)-6- C CI then CJ (400 MHz, METHANOL-d₄) δ: 0.78-0.84(m, 2 H), 0.94-1.00 (m, 2 H), 3 m/z 378 [cyclopropyl(methyl)carbamoyl]-69 and 79 1.23-1.32 (m, 3 H), 1.51-1.62 (m, 2 H), 1.89-1.94 (m, 2 H), E(M + H)⁺ 3-azabicyclo[3.1.0]hexan-3- 2.26-2.39 (m, 2 H), 2.48-2.57 (m, 2H), 2.65-2.69 (m, 1 H), 2.84- (ES⁺), at yl}-3-oxa-9- 2.93 (m, 3 H),3.10-3.21 (m, 2 H), 3.47-3.71 (m, 6H), 4.10-4.24 2.79 min,azabicyclo[3.3.1]nonane-9- (m, 4 H). 202 nm carboxylate 10-8 Isomer 2:ethyl 7-{(1R,5S,6r)-6- C CI then CJ (400 MHz, METHANOL-d₄) δ: 0.76-0.85(m, 2 H), 0.91-1.03 (m, 2 H), 3 m/z 378 [cyclopropyl(methyl)carbamoyl 69and 79 1.22-1.33 (m, 3 H), 1.54-1.69 (m, 2 H), 1.88-1.97 (m, 2 H), E(M + H)⁺ ]-3-azabicyclo[3.1.0]hexan-3- 1.99-2.12 (m, 2 H), 2.48-2.59 (m,2 H), 2.61-2.67 (m, 1 H), 2.89 (ES⁺), at yl}-3-oxa-9- (s, 3 H),3.10-3.20 (m, 2 H), 3.33-3.45 (m, 2 H), 3.61-3.73 (m, 2 H), 2.88 min,azabicyclo[3.3.1]nonane-9- 3.77-3.89 (m, 2 H), 4.02-4.11 (m, 2 H),4.11-4.21 (m, 2 H). 202 nm carboxylate 10-9 Isomer 1: ethyl7-{(1R,5S,6r)-6- C CK (400 MHz, METHANOL-d₄) δ: 0.79-0.85 (m, 2 H),0.97-1.06 (m, 2 H), 3 m/z 392 [cyclopropyl(ethyl)carbamoyl]- 69 and 191.06-1.17 (m, 3 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.48-1.68 (m, 2 H), E(M + H)⁺ 3-azabicyclo[3.1.0]hex-3-yl}-3- 1.91-1.96 (m, 2 H), 2.01 (tt, J= 11.6, 5.8 Hz, 1 H), 2.24-2.43 (m, 2 H), (ES⁺), at oxa-9- 2.53 (d, J =9.2 Hz, 2 H), 2.66-2.71 (m, 1 H), 2.83-3.03 (m, 1 H), 3.09 min,azabicyclo[3.3.1]nonane-9- 3.18 (d, J = 9.2 Hz, 2 H), 3.43 (q, J = 6.9Hz, 2 H), 3.48-3.69 (m, 4 H), 202 nm carboxylate 4.10-4.27 (m, 4 H).10-9 Isomer 2: ethyl 7-{(1R,5S,6r)-6- C CK (400 MHz, METHANOL-d₄) δ:0.78-0.85 (m, 2 H), 0.97-1.05 (m, 2 H), 1.12 3 m/z 392[cyclopropyl(ethyl)carbamoyl]- 69 and 19 (t, J = 7.0 Hz, 3 H), 1.28 (t,J = 7.0 Hz, 3 H), 1.55-1.71 (m, 2 H), 1.92-1.97 E (M + H)⁺3-azabicyclo[3.1.0]hex-3-yl}-3- (m, 2 H), 2.06 (dd, J = 12.8, 5.5 Hz, 2H), 2.56 (d, J = 9.2 (ES⁺), at oxa-9- Hz, 2 H), 2.63-2.67 (m, 1 H),2.80-2.92 (m, 1 H), 3.17 (dd, J = 9.5, 3.15 min,azabicyclo[3.3.1]nonane-9- 4.0 Hz, 2 H), 3.36-3.46 (m, 3 H), 3.63-3.76(m, 2 H), 3.80-3.92 (m, 202 nm carboxylate 2 H), 4.04-4.13 (m, 2 H),4.17 (q, J = 6.9 Hz, 2 H). 10-10 Isomer 1: methyl 7-{(1R,5S,6r)-6- C CLthen CM (400 MHz, METHANOL-d₄) δ: 0.76-0.86 (m, 2 H), 0.95-1.03 (m, 2H), 3 m/z 378 [cyclopropyl(ethyl)carbamoyl]- 71 and 19 1.06-1.15 (m, 3H), 1.51-1.63 (m, 2 H), 1.89-1.96 (m, 2 H), E (M + H)⁺3-azabicyclo[3.1.0]hexan-3- 1.98-2.09 (m, 1 H), 2.26-2.39 (m, 2 H),2.49-2.57 (m, 2 H), 2.63- (ES⁺), at yl}-3-oxa-9- 2.69 (m, 1 H),2.81-2.90 (m, 1 H), 3.11-3.22 (m, 2 H), 3.36-3.46 2.80 min,azabicyclo[3.3.1]nonane-9- (m, 2 H), 3.47-3.66 (m, 4 H), 3.71 (s, 3 H),4.14-4.24 (m, 2 H). 202 nm carboxylate 10-10 Isomer 2: methyl 7- C CLthen CM (400 MHz, METHANOL-d₄) δ: 0.77-0.84 (m, 2 H), 0.96-1.03 (m, 2H), 3 m/z 378 {(1R,5S,6r)-6- 71 and 19 1.06-1.14 (m, 3 H), 1.56-1.69 (m,2 H), 1.90-1.97 (m, 2 H), E (M + H)⁺ [cyclopropyl(ethyl)carbamoyl]-2.00-2.11 (m, 2 H), 2.54-2.66 (m, 3 H), 2.80-2.88 (m, 1 H), 3.12- (ES⁺),at 3-azabicyclo[3.1.0]hexan-3- 3.21 (m, 2 H), 3.35 (s, 1 H), 3.37-3.47(m, 2 H), 3.62-3.69 (m, 2 H), 2.83 min, yl}-3-oxa-9- 3.71 (s, 3 H),3.77-3.89 (m, 2 H), 4.03-4.12 (m, 2 H). 202 nmazabicyclo[3.3.1]nonane-9- carboxylate 10-11 Isomer 1: ethyl7-[(1R,5S,6r)- C CN then CO (400 MHz, METHANOL-d₄) δ: 1.25-1.34 (m, 4H), 1.51-1.68 3 m/z 392 6-(piperidin-1-ylcarbonyl)-3- 69 and 21 (m, 5H), 1.71 (d, J = 4.3 Hz, 2 H), 1.94-1.99 (m, 2 H), 2.05-2.17 (m, 1 H), E(M + H)⁺ azabicyclo[3.1.0]hex-3-yl]-3- 2.27-2.42 (m, 3 H), 2.61 (d, J =7.9 Hz, 2 H), 3.23 (d, J = 9.8 Hz, 2 H), (ES⁺), at oxa-9- 3.51-3.72 (m,8 H), 4.12-4.27 (m, 4 H). 3.16 min, azabicyclo[3.3.1]nonane-9- 202 nmcarboxylate 10-11 Isomer 2: ethyl 7-[(1R,5S,6r)- C CN then CO (400 MHz,METHANOL-d₄) δ: 1.29 (t, J = 7.0 Hz, 3 H), 1.50-1.75 (m, 3 m/z 3926-(piperidin-1-ylcarbonyl)-3- 69 and 21 7 H), 1.94-2.00 (m, 2 H), 2.08(dd, J = 12.8, 4.9 Hz, 2 H), 2.24-2.29 E (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-3- (m, 1 H), 2.62 (d, J = 9.2 Hz, 2 H), 3.21(dd, J = 9.2, 4.3 Hz, 2 H), 3.37 (ES⁺), at oxa-9- (s, 1 H), 3.42-3.62(m, 3 H), 3.62-3.74 (m, 4 H), 3.79-3.94 (m, 2 H), 3.19 min,azabicyclo[3.3.1]nonane-9- 4.06-4.13 m, 2 H), 4.17 (q, J = 7.1 Hz, 2 H).202 nm carboxylate 10-12 Isomer 1: methyl 7- C CP then CQ (400 MHz,METHANOL-d₄) δ: 1.48-1.59 (m, 4 H), 1.60-1.66 (m, 2 H), 3 m/z 378[(1R,5S,6r)-6-(piperidine-1- 71 and 21 1.66-1.74 (m, 2 H), 1.89-1.93 (m,2 H), 1.94-2.06 (m, 1 H), E (M + H)⁺ carbonyl)-3- 2.25-2.38 (m, 3 H),2.46-2.52 (m, 2 H), 3.11-3.18 (m, 2 H), 3.46- (ES⁺), atazabicyclo[3.1.0]hexan-3-yl]- 3.56 (m, 5 H), 3.57-3.60 (m, 1 H),3.64-3.69 (m, 2 H), 3.70 (s, 3 H), 2.80 min, 3-oxa-9- 4.14-4.24 (m, 2H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-12 Isomer 2: methyl7- C CP then CQ (400 MHz, METHANOL-d₄) δ: 1.47-1.55 (m, 2 H), 1.56-1.66(m, 4 H), 3 m/z 378 [(1R,5S,6r)-6-(piperidine-1- 71 and 21 1.66-1.74 (m,2 H), 1.89-1.95 (m, 2 H), 2.00-2.09 (m, 2 H), E (M + H)⁺ carbonyl)-3-2.22-2.27 (m, 1 H), 2.47-2.54 (m, 2 H), 3.09-3.16 (m, 2 H), 3.33- (ES⁺),at azabicyclo[3.1.0]hexan-3-yl]- 3.41 (m, 1 H), 3.49-3.55 (m, 2 H),3.61-3.69 (m, 4 H), 3.71 (s, 3 H), 2.83 min, 3-oxa-9- 3.78-3.88 (m, 2H), 4.03-4.10 (m, 2 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate10-13 Isomer 1: ethyl 7-[(1R,5S,6r)- C CR then CS (400 MHz, METHANOL-d₄)δ: 1.26 (s, 3 H), 1.62-1.74 (m, 2 H), 2.00- 3 m/z 3946-(morpholine-4-carbonyl)-3- 69 and 80 2.09 (m, 2 H), 2.21-2.27 (m, 1H), 2.28-2.40 (m, 2 H), 2.64-2.87 E (M + H)⁺azabicyclo[3.1.0]hexan-3-yl]- (m, 2 H), 3.23-3.29 (m, 2 H), 3.35 (s, 2H), 3.52-3.60 (m, 4 H), 3.61- (ES⁺), at 3-oxa-9- 3.66 (m, 2 H),3.66-3.70 (m, 2 H), 3.71 (s, 3 H), 4.11-4.19 (m, 2 H), 2.55 min,azabicyclo[3.3.1]nonane-9- 4.19-4.26 (m, 2 H). 202 nm carboxylate 10-13Isomer 2: ethyl 7-[(1R,5S,6r)- C CR then CS (400 MHz, METHANOL-d₄) δ:1.27 (t, J = 7.09 Hz, 3 H), 1.58-1.72 (m, 3 m/z 3946-(morpholine-4-carbonyl)-3- 69 and 80 2 H), 2.00-2.06 (m, 2 H),2.07-2.15 (m, 2 H), 2.22-2.27 (m, 1 H), E (M + H)⁺azabicyclo[3.1.0]hexan-3-yl]- 2.67-2.91 (m, 2 H), 3.22-3.30 (m, 2 H),3.35 (s, 2 H), 3.53-3.59 (ES⁺), at 3-oxa-9- (m, 2 H), 3.60-3.66 (m, 2H), 3.67-3.70 (m, 2 H), 3.70 (s, 3 H), 3.80- 2.59 min,azabicyclo[3.3.1]nonane-9- 3.90 (m, 2 H), 4.08-4.19 (m, 4 H). 202 nmcarboxylate 10-14 Isomer 1: ethyl 7-[(1R,5S,6r)- C CT (400 MHz,METHANOL-d₄) δ: 1.28 (t, J = 7.0 Hz, 3 H), 1.51-1.67 (m, 3 m/z 4066-(azepan-1-ylcarbonyl)-3- 69 and 24 6H), 1.71 (dt, J = 11.3, 6.0 Hz, 2H), 1.76-1.88 (m, 2 H), 1.93-1.97 E (M + H)⁺azabicyclo[3.1.0]hex-3-yl]-3- (m, 2 H), 1.97-2.13 (m, 1 H), 2.20-2.42(m, 3 H), 2.42-2.59 (m, 2 H), (ES⁺), at oxa-9- 3.11-3.23 (m, 2 H),3.49-3.76 (m, 8 H), 4.06-4.28 (m, 4 H). 3.48 min,azabicyclo[3.3.1]nonane-9- 202 nm carboxylate 10-14 Isomer 2: ethyl7-[(1R,5S,6r)- C CT (400 MHz, METHANOL-d₄) δ: 1.28 (t, J = 7.0 Hz, 3 H),1.52-1.67 (m, 3 m/z 406 6-(azepan-1-ylcarbonyl)-3- 69 and 24 6H), 1.71(dt, J = 11.3, 6.0 Hz, 2 H), 1.81 (quin, J = 5.8 Hz, 2 H), 1.93- E (M +H)⁺ azabicyclo[3.1.0]hex-3-yl]-3- 1.98 (m, 2 H), 2.06 (dd, J = 12.8, 5.5Hz, 2 H), 2.23-2.28 (m, 1 H), (ES⁺), at oxa-9- 2.54 (d, J = 9.2 Hz, 2H), 3.16 (dd, J = 9.8, 5.5 Hz, 2 H), 3.35-3.46 (m, 3.58 min,azabicyclo[3.3.1]nonane-9- 1 H), 3.51 (t, J = 6.1 Hz, 2 H), 3.62-3.76(m, 4 H), 3.79-3.95 202 nm carboxylate (m, 2 H), 4.06-4.13 (m, 2 H),4.17 (q, J = 7.3 Hz, 2 H). 10-15 Isomer 1: ethyl 7-[(1R,5S,6r)- C CU(400 MHz, METHANOL-d₄) δ: 1.28 (t, J = 7.0 Hz, 3 H), 1.50-1.78 (m, 3 m/z404 6-(1-azaspiro[3.3]hept-1- 69 and 28 2 H), 1.78-1.89 (m, 2 H),1.90-1.95 (m, 1 H), 1.97-2.12 (m, 3 H), E (M + H)⁺ ylcarbonyl)-3-2.16-2.24 (m, 1 H), 2.25-2.42 (m, 3 H), 2.43-2.58 (m, 3 H), 2.77- (ES⁺),at azabicyclo[3.1.0]hex-3-yl]-3- 3.00 (m, 2 H), 3.11-3.24 (m, 2 H),3.36-3.42 (m, 1 H), 3.49-3.72 3.34 min, oxa-9- (m, 3 H), 3.75-3.91 (m, 2H), 4.05-4.26 (m, 5 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate10-15 Isomer 2: ethyl 7-[(1R,5S,6r)- C CU (400 MHz, METHANOL-d₄) δ: 1.28(t, J = 7.0 Hz, 3 H), 1.56-1.89 (m, 3 m/z 404 6-(1-azaspiro[3.3]hept-1-69 and 28 4 H), 1.90-1.95 (m, 1 H), 1.96-2.14 (m, 4 H), 2.15-2.31 (m, 1H), E (M + H)⁺ ylcarbonyl)-3- 2.34-2.49 (m, 2 H), 2.49-2.67 (m, 2 H),2.75-3.04 (m, 2 H), 3.16 (ES⁺), at azabicyclo[3.1.0]hex-3-yl]-3- (ddd, J= 19.7, 9.6, 4.9 Hz, 2 H), 3.36-3.50 (m, 1 H), 3.41 min, oxa-9-3.62-3.73 (m, 3 H), 3.74-3.92 (m, 3 H), 4.04-4.25 (m, 5 H). 202 nmazabicyclo[3.3.1]nonane-9- carboxylate 11-1 Isomer 1: ethyl4-[(1R,5S,6r)- C CV then CW (400 MHz, METHANOL-d₄) δ: 1.05 (t, J = 7.09Hz, 3 H), 1.16-1.26 (m, 3 m/z 352 6-(diethylcarbamoyl)-3- 82 and 4 6H),1.41-1.68 (m, 3 H), 1.75-1.94 (m, 5 H), 2.15 (t, J = 2.93 Hz, 1 H), E(M + H)⁺ azabicyclo[3.1.0]hexan-3- 2.28-2.36 (m, 1 H), 2.45-2.51 (m, 2H), 3.05-3.13 (m, 2 H), (ES⁺), at yl]azepane-1-carboxylate 3.24-3.36 (m,4 H), 3.36-3.43 (m, 1 H), 3.44-3.55 (m, 3 H), 4.03- 3.41 min, 4.13 (m, 2H). 202 nm 11-1 Isomer 2: ethyl 4-[(1R,5S,6r)- C CV then CW (400 MHz,METHANOL-d₄) δ: 0.97-1.13 (m, 3 H), 1.16-1.27 3 m/z 3526-(diethylcarbamoyl)-3- 82 and 4 (m, 6H), 1.42-1.68 (m, 3 H), 1.76-1.93(m, 4 H), 2.13-2.17 (m, 1 H), E (M + H)⁺ azabicyclo[3.1.0]hexan-3-2.27-2.37 (m, 1 H), 2.44-2.54 (m, 2 H), 3.04-3.14 (m, 2 H), 3.22- (ES⁺),at yl]azepane-1-carboxylate 3.37 (m, 5 H), 3.37-3.44 (m, 1 H), 3.43-3.56(m, 3 H), 4.04-4.11 3.41 min, (m, 2 H). 202 nm 11-2 Isomer 1: ethyl3-[(1R,5S,6r)- C CX (400 MHz, METHANOL-d₄) δ: 1.09 (t, J = 7.02 Hz, 3H), 1.18-1.33 (m, 4 m/z 364 6-(diethylcarbamoyl)-3- 85 and 4 7 H),1.39-1.49 (m, 1 H), 1.53-1.62 (m, 1 H), 1.78-2.01 (m, 4 H), C (M + H)⁺azabicyclo[3.1.0]hexan-3-yl]- 2.14-2.24 (m, 2 H), 2.27-2.38 (m, 1 H),2.40-2.54 (m, 3 H), 3.10 (ES⁺), at 6-azabicyclo[3.2.1]octane-6- (dd, J =9.61, 5.95 Hz, 2 H), 3.20-3.29 (m, 1 H), 3.29-3.43 (m, 3 H), 3.29 min,carboxylate 3.43-3.61 (m, 2 H), 4.05-4.19 (m, 3 H). 202 nm 11-2 Isomer2: ethyl 3-[(1R,5S,6r)- C CX (400 MHz, METHANOL-d₄) δ: 1.03-1.14 (m, 3H), 1.21-1.31 (m, 6 H), 4 m/z 364 6-(diethylcarbamoyl)-3- 85 and 41.50-1.59 (m, 1 H), 1.61-1.77 (m, 2 H), 1.80-1.92 (m, 3 H), C (M + H)⁺azabicyclo[3.1.0]hexan-3-yl]- 2.01-2.24 (m, 3 H), 2.26-2.37 (m, 2 H),2.44-2.53 (m, 1 H), 3.10- (ES⁺), at 6-azabicyclo[3.2.1]octane-6- 3.40(m, 6 H), 3.40-3.56 (m, 2 H), 3.75-3.88 (m, 1 H), 3.94-4.05 4.36 min,carboxylate (m, 1 H), 4.07-4.24 (m, 2 H). 202 nm 12-1 Isomer 1: ethyl5-[(1R,5S,6r)- C CZ (400 MHz, METHANOL-d₄) δ: 1.08 (t, J = 7.10 Hz, 3H), 1.24 (t, J = 7.10 3 m/z 364 6-(diethylcarbamoyl)-3- 88 and 4 Hz, 6H), 1.27-1.36 (m, 2 H), 1.86-1.94 (m, 2 H), 2.07-2.18 (m, 2 H), E (M +H)⁺ azabicyclo[3.1.0]hexan-3- 2.21-2.27 (m, 1 H), 2.49 (d, J = 9.31 Hz,2 H), 2.55-2.72 (m, 3 H), (ES⁺), at yl]hexahydrocyclopenta[c]pyrrole-3.12 (d, J = 9.61 Hz, 2 H), 3.31-3.40 (m, 4 H), 3.41-3.59 (m, 4 H), 3.35min, 2(1H)-carboxylate 4.09 (q, J = 7.02 Hz, 2 H). 202 nm 12-1 Isomer 2:ethyl 5-[(1R,5S,6r)- C CZ (400 MHz, METHANOL-d₄) δ: 1.09 (t, J = 7.10Hz, 3 H), 1.25 (t, J = 7.10 3 m/z 364 6-(diethylcarbamoyl)-3- 88 and 4Hz, 6 H), 1.28-1.36 (m, 2 H), 1.88-1.94 (m, 2 H), 2.09-2.18 (m, 2 H), E(M + H)⁺ azabicyclo[3.1.0]hexan-3- 2.22-2.26 (m, 1 H), 2.50 (d, J = 9.31Hz, 2 H), 2.56-2.71 (m, 3 H), (ES⁺), atyl]hexahydrocyclopenta[c]pyrrole- 3.12 (d, J = 9.61 Hz, 2 H), 3.32-3.40(m, 4 H), 3.42-3.49 (m, 2 H), 3.36 min, 2(1H)-carboxylate 3.53 (q, J =7.17 Hz, 2 H), 4.10 (q, J = 7.17 Hz, 2 H). 202 nm

Biological Activity Example A Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefirephospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High ThroughputScreen, 2008). ERK1/2 phosphorylation is a downstream consequence ofboth Gq/11 and Gi/o protein coupled receptor activation, making ithighly suitable for the assessment of M₁, M₃ (Gq/11 coupled) and M₂, M₄receptors (Gi/o coupled), rather than using different assay formats fordifferent receptor subtypes. CHO cells stably expressing the humanmuscarinic M₁, M₂, M₃ or M₄ receptor were plated (25K/well) onto 96-welltissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cellswere serum-starved overnight. Agonist stimulation was performed by theaddition of 5 μL agonist to the cells for 5 min (37° C.). Media wasremoved and 50 μL of lysis buffer added. After 15 min, a 4 μL sample wastransferred to 384-well plate and 7 μL of detection mixture added.Plates were incubated for 2 h with gentle agitation in the dark and thenread on a PHERAstar plate reader. pEC₅₀ and E_(max) figures werecalculated from the resulting data for each receptor subtype and theresults are set out in Table 4 below.

For the vast majority of examples at least two diastereomers exist andthese have been separated, unless otherwise stated, using the techniquesof reversed phase HPLC, chiral HPLC or chiral SFC. Isomer assignment(Isomer 1, Isomer 2, etc.) is based on the retention time of thecompound using the separation technique that was performed in the finalpurification step. By implication, this could be reversed phase HPLC,chiral HPLC or chiral SFC retention time, and this will vary fromcompound to compound.

Analytical data for active isomers is reported in Table 3. Data forseveral weakly active compounds are included in Table 4 to highlight thepreference for absolute stereochemistry.

TABLE 4 Muscarinic Activity pEC₅₀ M₁ pEC₅₀ M₂ pEC₅₀ M₃ pEC₅₀ M₄ (% Emax(% Emax (% Emax (% Emax Example No. cf. ACh) cf. ACh) cf. ACh) cf. ACh)ACh 8.05 (96) 7.74 (106) 8.27 (104) 7.99 (109) 1-1 5.03 (115) <4.70 (12)<4.70 (6) 6.50 (73) 1-2 6.88 (110) NT NT 6.02 (81) 1-4 5.34 (55) NT NT6.21 (47) 2-1 Mixture of isomers <4.70 (22) <4.70 (7) <4.70 (0) 7.11(86) 2-2 Isomer 1 6.41 (69) NT NT 5.62 (43) 2-2 Isomer 2 7.10 (101)<4.70 (8) <4.70 (2) 6.56 (63) 2-3 Isomer 1 7.39 (108) <4.70 (14) <4.70(15) 6.77 (100) 2-3 Isomer 2 6.83 (90) NT NT 5.97 (66) 2-4 Isomer 1 5.64(49) NT NT 5.97 (37) 2-4 Isomer 2 7.27 (112) <4.70 (18) <4.70 (1) 6.81(94) 2-5 Isomer 1 <4.70 (26) NT NT 5.71 (37) 2-5 Isomer 1 7.25 (107)<4.70 (9) <4.70 (20) 6.72 (85) 2-6 Isomer 1 5.90 (42) NT NT <4.70 (39)2-7 Isomer 1 5.80 (66) NT NT 5.60 (50) 2-8 Isomer 1 6.06 (50) NT NT 5.78(37) 2-8 Isomer 2 7.52 (110) <4.70 (15) <4.70 (17) 7.00 (92) 2-9 Isomer1 6.39 (57) NT NT 5.96 (28) 2-10 Isomer 1 5.93 (66) NT NT <4.70 (56)2-11 Mixture of isomers 7.69 (100) <4.70 (20) <4.70 (1615) 7.17 (85)2-12 Isomer 1 4.88 (65) NT NT 6.14 (85) 2-12 Isomer 2 6.67 (79) NT NT6.37 (72) 2-13 Isomer 1 6.72 (31) NT NT <4.70 (71) 2-13 Isomer 2 6.94(83) <4.70 (51) <4.70 (38) 6.32 (72) 2-14 Isomer 1 6.49 (80) NT NT 5.91(33) 2-14 Isomer 2 7.72 (111) <4.70 (62) 4.85 (100) 7.16 (93) 2-16Isomer 1 7.29 (30) <4.70 (53) <4.70 (45) <4.70 (11) 2-16 Isomer 2 7.79(94) <4.70 (87) <4.70 (59) 7.42 (75) 2-17 Isomer 1 6.28 (44) NT NT <4.70(13) 2-17 Isomer 2 7.19 (96) <4.70 (7) <4.70 (20) 6.55 (63) 2-18 Mixtureof isomers <4.70 (11) NT NT 6.04 (34) 2-19 Isomer 2 7.88 (93) <4.70 (16)<4.70 (35) 7.43 (95) 2-21 Isomer 1 6.34 (67) NT NT 5.92 (43) 2-22 Isomer2 5.76 (95) NT NT 5.67 (71) 2-23 Isomer 2 6.79 (129) NT NT 6.45 (95)2-24 Isomer 1 6.03 (76) NT NT 5.79 (53) 2-24 Isomer 2 7.47 (115) <4.70(11) 4.73 (47) 7.30 (102) 2-25 Isomer 2 5.89 (37) NT NT 6.36 (35) 2-25Isomer 4 6.49 (65) <4.70 (24) <4.70 (4) 6.82 (48) 2-26 Mixture ofisomers 5.86 (52) <4.70 (8) <4.70 (12) 7.31 (114) 2-27 Mixture ofisomers <4.70 (20) NT NT 5.83 (32) 2-28 Isomer 1 6.24 (58) NT NT <4.70(21) 2-28 Isomer 2 7.19 (104) <4.70 (7) <4.70 (5) 7.27 (51) 2-29 Isomer2 6.19 (43) <4.70 (36) <4.70 (2) 7.06 (83) 2-30 Isomer 1 <4.70 (29) NTNT 6.45 (61) 2-30 Isomer 2 6.85 (86) <4.70 (34) <4.70 (7) 7.57 (88) 3-1Mixture of isomers <4.70 (21) <4.70 (4) <4.70 (2) 7.89 (62) 3-2 Mixtureof isomers 8.32 (92) <4.70 (20) <4.70 (21) 7.79 (79) 4-1 6.63 (84) NT NT6.15 (35) 5-1 Isomer 1 5.21 (78) NT NT 6.53 (81) 5-1 Isomer 2 <4.70(102) NT NT 6.09 (54) 5-2 Isomer 1 7.00 (134) <4.70 (10) NT 5.58 (95)6-1 Isomer 2 6.46 (76) NT NT <4.70 (2) 7-1 Isomer 2 5.67 (83) NT NT 5.80(62) 7-2 Isomer 1 6.11 (116) NT NT <4.70 (14) 7-2 Isomer 2 6.66 (113) NTNT 4.96 (53) 7-3 Isomer 1 6.78 (123) NT NT 5.58 (45) 7-5 Isomer 2 <4.70(23) NT NT 6.13 (38) 7-6 Isomer 2 5.94 (56) NT NT 6.21 (73) 8-1 Mixtureof isomers 5.78 (53) NT NT 6.26 (61) 8-2 Isomer 2 6.20 (134) NT NT 5.20(52) 8-3 Isomer 1 5.83 (104) NT NT 5.49 (29) 8-4 Isomer 1 6.13 (89) NTNT <4.70 (4) 8-5 Isomer 1 6.89 (106) <4.70 (6) <4.70 (6) 5.72 (47) 8-5Isomer 2 7.05 (39) <4.70 (2) <4.70 (5) <4.70 (12) 8-6 Isomer 1 6.07 (31)NT NT <4.70 (2) 8-6 Isomer 2 6.45 (39) NT NT <4.70 (2) 8-9 Isomer 1 6.43(99) NT NT <4.70 (7) 8-10 Isomer 1 7.87 (117) <4.70 (7) <4.70 (21) 7.13(52) 8-10 Isomer 2 6.03 (123) NT NT <4.70 (16) 9-1 Isomer 1 7.04 (93)<4.70 (19) <4.70 (21) 6.06 (57) 9-1 Isomer 2 6.01 (93) NT NT <4.70 (24)9-2 Isomer 1 6.56 (102) NT NT 5.87 (41) 9-3 Isomer 1 6.40 (106) NT NT6.12 (60) 10-1 Isomer 1 5.94 (110) NT NT <4.70 (24) 10-1 Isomer 1 5.76(78) NT NT <4.70 (15) 10-2 Isomer 2 7.15 (113) <4.70 (25) <4.70 (10)6.04 (62) 10-3 Isomer 1 6.67 (96) NT NT 6.24 (73) 10-3 Isomer 2 5.75(81) NT NT <4.70 (25) 10-5 Isomer 1 6.30 (99) NT NT 5.91 (81) 10-5Isomer 2 5.66 (101) NT NT 4.90 (90) 10-7 Isomer 1 7.42 (99) NT NT 6.79(69) 10-7 Isomer 2 6.83 (100) NT NT 6.23 (64) 10-8 Isomer 1 5.99 (116)NT NT 4.84 (47) 10-8 Isomer 2 5.65 (85) NT NT 5.67 (32) 10-9 Isomer 26.57 (105) NT NT 5.47 (38) 10-10 Isomer 1 NT NT NT NT 10-10 Isomer 2 NTNT NT NT 10-12 Isomer 2 5.99 (99) NT NT 4.85 (86) 10-13 Isomer 1 6.51(104) <4.70 (24) <4.70 (68) 5.95 (64) 10-13 Isomer 2 6.43 (101) <4.70(24) <4.70 (22) 4.99 (59) 11-1 Isomer 1 7.98 (97) NT NT 6.90 (84) 11-1Isomer 2 7.43 (94) NT NT 6.33 (62) 11-2 Isomer 1 6.41 (37) NT NT <4.70(3) 11-2 Isomer 2 6.93 (113) <4.70 (5) <4.70 (3) 6.02 (65) 12-1 Isomer 16.21 (49) NT NT <4.70 (6) 12-1 Isomer 2 5.94 (49) NT NT <4.70 (8)

1. A method of treating a cognitive disorder or psychotic disorder orfor treating or lessening the severity of acute, chronic, neuropathic,or inflammatory pain in a subject, comprising administering to thesubject an effective amount of a compound of the formula (1):

or a salt thereof, wherein: X¹ and X² are saturated hydrocarbon groupswhich together contain a total of five to nine carbon atoms and zero orone oxygen atoms and which link together such that the moiety:

forms a monocyclic or bicyclic ring system optionally substituted withone or more fluorine atoms; R¹ is selected from OR⁵; NR⁵R⁶; COR⁵; COOR⁵;CONR⁵R⁶; CONR⁵OR⁶; C(═NR⁵)R⁶; C(═NOR⁵)R⁶; OCOR⁵; NR⁷COR⁵; NR⁷CONR⁵R⁶;NR⁷COOR⁵; OCONR⁵R⁶; CH₂OR⁵; CH₂NR⁵R⁶; CH₂COR⁵; CH₂COOR⁵; CH₂CONR⁵R⁶;CH₂CONR⁵OR⁶; CH₂C(═NR⁵)R⁶; CH₂C(═NOR⁵)R⁶; CH₂OCOR⁵; CH₂NR⁷COR⁵;CH₂NR⁷CONR⁵R⁶; CH₂NR⁷COOR⁵; CH₂OCONR⁵R⁶; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof; and an optionally substituted 4, 5- or6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, Nand S and oxidized forms thereof; R⁴ is H or a C₁₋₆ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one or two, but not all, carbon atoms of thehydrocarbon group may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidised forms thereof; and R⁵, R⁶ and R⁷ are thesame or different and each is independently selected from hydrogen, anon-aromatic C₁₋₆ hydrocarbon group optionally substituted with one ormore fluorine atoms or optionally substituted with a 4, 5- or 6-memberedring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof, or R⁵ and R⁶ can be joined together to form anoptionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or3 heteroatoms selected from O, N and S and oxidized forms thereof. 2.The method according to claim 1 wherein R¹ is selected from OR⁵; NR⁵R⁶;COOR⁵; CONR⁵R⁶; CONR⁵OR⁶; C(═NOR⁵)R⁶; CH₂NR⁷COR⁵; a C₁₃ alkyl groupwhich is optionally substituted with one to three fluorine atoms; and anoptionally substituted 4, 5- or 6-membered ring containing 1, or 2heteroatoms selected from O, N and S and oxidized forms thereof.
 3. Themethod according to claim 1 wherein R¹ is selected from COOR⁵; CONR⁵R⁶;CONR⁵OR⁶; C(═NOR⁵)R⁶; and an optionally substituted 5-membered ringcontaining 1, or 2 heteroatoms selected from O, N and S and oxidizedforms thereof.
 4. The method according to claim 1 wherein R¹ is selectedfrom COOR⁵ and CONR⁵R⁶.
 5. The method according to claim 1 wherein R⁵ isselected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon group optionallysubstituted with one or more fluorine atoms or optionally substitutedwith a 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof, or R⁵ and R⁶ can bejoined together to form an optionally substituted monocyclic or bicyclicring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof.
 6. The method according to claim 1 wherein R⁶ isselected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon group optionallysubstituted with one or more fluorine atoms or optionally substitutedwith a 4, 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof, or R⁵ and R⁶ can bejoined together to form an optionally substituted monocyclic or bicyclicring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof.
 7. The method according to claim 1 wherein R¹ isCOOR⁵ wherein R⁵ is a non-aromatic C₁₋₆ hydrocarbon group or R¹ isCONR⁵R⁶ wherein R⁵ is a non-aromatic C₁₋₆ hydrocarbon group and R⁶ isselected from hydrogen and a non-aromatic C₁₋₆ hydrocarbon group, or R¹is CONR⁵R⁶ and R⁵ and R⁶ are joined together to form an optionallysubstituted monocyclic or bicyclic ring containing. 0, 1, 2 or 3heteroatoms selected from O, N and S and oxidized forms thereof, or R¹is CONR⁵OR⁶ wherein R⁵ is a non-aromatic C₁₋₆ hydrocarbon group and R⁶is a non-aromatic C₁₋₆ hydrocarbon group.
 8. The method according toclaim 1 wherein R¹ is selected from NR⁵R⁶; CONR⁵R⁶; and CH₂NR⁵R⁶; and R⁵and R⁶ are joined together to form an optionally substituted monocyclicor bicyclic ring containing. 0, 1, 2 or 3 heteroatoms selected from O, Nand S and oxidized forms thereof.
 9. The method according to claim 1wherein R¹ is selected from the group consisting of:


10. The method according to claim 1 wherein R⁴ is selected from thegroup consisting of H, methyl, ethyl, ethynyl and 1-propynyl.
 11. Themethod according to claim 10 wherein R⁴ is H.
 12. The method accordingto claim 1 wherein the bicyclic ring system formed by the moiety:

is selected from ring systems below:


13. The method according to claim 1, wherein the compound is a compoundof the formula (2):

wherein n is 1 or
 2. 14. The method according to claim 1 wherein thecompound is selected from the group consisting of: ethyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate;ethyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate;ethyl6-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azaspiro[3.3]heptane-2-carboxylate;ethyl6-[(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate;ethyl2-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[(2-methylpropyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[(cyclobutylmethyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[(1-methylcyclobutyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[ethyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;methyl2-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[methyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;methyl2-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[cyclopropyl(ethyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(pyrrolidin-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(piperidin-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-{[(2R)-2-methylpiperidin-1-yl]carbonyl}-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-{[(2S)-2-methylpiperidin-1-yl]carbonyl}-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(azepan-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(1,4-oxazepan-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(2-azaspiro[3.3]hept-2-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(1-azaspiro[3.3]hept-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;methyl2-[(1R,5S,6r)-6-(1-azaspiro[3.3]hept-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(6-oxa-1-azaspiro[3.3]hept-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6r)-6-[ethyl(methoxy)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[6-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-{(1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl}-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl2-[(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate;ethyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate;ethyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate;methyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate;ethyl6-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azaspiro[3.4]octane-2-carboxylate;ethyl4-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]piperidine-1-carboxylate;ethyl6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate;ethyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate;ethyl8-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-azabicyclo[3.2.1]octane-3-carboxylate;ethyl3-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-{(1R,5S,6r)-6-[ethyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl3-[(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate;ethyl5-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl (1S,4S)-5-{(1R,5S,6r)-6-[ethyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl(1R,4R)-5-{(1R,5S,6r)-6-[ethyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl}-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl (1S,4S)-5-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl(1R,4R)-5-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate;methyl5-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl (1S,4S)-5-{(1R,5S,6r)-6-[cyclopropyl(ethyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-{(1R,5S,6r)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl}-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl5-{(1R,5S,6r)-6-[ethyl(methoxy)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azabicyclo[2.2.2]octane-2-carboxylate;ethyl3-{(1R,5S,6r)-6-[ethyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl3-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-9-azabicyclo[3.3.1]nonane-9-carboxylate;methyl3-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-{(1R,5S,6r)-6-[ethyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;methyl7-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-{(1R,5S,6r)-6-[methyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;methyl7-((1R,5S,6r)-6-(isopropyl(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;methyl7-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-{(1R,5S,6r)-6-[cyclopropyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-{(1R,5S,6r)-6-[cyclopropyl(ethyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;methyl7-{(1R,5S,6r)-6-[cyclopropyl(ethyl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-[(1R,5S,6r)-6-(piperidin-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;methyl7-[(1R,5S,6r)-6-(piperidine-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-[(1R,5S,6r)-6-(morpholine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-[(1R,5S,6r)-6-(azepan-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl7-[(1R,5S,6r)-6-(1-azaspiro[3.3]hept-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate;ethyl4-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]azepane-1-carboxylate;ethyl3-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azabicyclo[3.2.1]octane-6-carboxylate;and ethyl5-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,or salts thereof.
 15. The method according to claim 13 wherein thecompound is methyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylateor a salt thereof.
 16. The method according to claim 13 wherein thecompound is ethyl6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylateor a salt thereof.
 17. The method according to claim 13 wherein thecompound is methyl7-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylateor a salt thereof.
 18. The method according to claim 1, wherein thecognitive disorder is Alzheimer's disease.
 19. The method according toclaim 1, wherein the cognitive disorder is dementia with Lewy bodies.20. The method according to claim 1, wherein the psychotic disorder isschizophrenia.